Substituted cyclic compounds, preparation method and pharmaceutical compositions containing them

ABSTRACT

The invention concerns compounds of formula (1): R-A-R′ wherein: A is as defined in the description; R represent a group (V), (VI), (VII), or (VIII), where E, Q, R 1 , R 2 , R 3 , v and R 4  are as defined in the description; R′ represents a —(CH 2 ) t —R 5  group wherein t and R 5  are as defined in the description, and medicaments containing the same.

FIELD OF THE INVENTION

[0001] The present invention relates to new substituted cyclic compoundshaving very valuable pharmacological characteristics in respect ofmelatoninergic receptors.

DESCRIPTION OF THE PRIOR ART

[0002] The prior art discloses retroamide chain indoles substituted byamides or carbamates for use as antagonists of GnRH (WO 9721707) andamide chain indoles substituted by amides, carbamates or ureas for useas antihypertensive agents (U.S. Pat. No. 4,803,218).

[0003] Retroamide chain benzofuran and benzothiophene compoundssubstituted by amides or carbamates have also been described asanti-inflammatory agents (EP 685475) or inhibitors of bone resorption.

BACKGROUND OF THE INVENTION

[0004] In the last ten years, numerous studies have demonstrated themajor role played by melatonin (5-methoxy-N-acetyltryptamine) innumerous physiopathological phenomena and also in the control ofcircadian rhythm. Its half-life is, however, quite short owing to itsbeing rapidly metabolised. It is thus very useful to be able to providethe clinician with melatonin analogues that are metabolically morestable and that have an agonist or antagonist character on the basis ofwhich a therapeutic effect that is superior to that of the hormoneitself may be expected.

[0005] In addition to their beneficial action on disorders of circadianrhythm (J. Neurosurg. 1985, 63. pp 321-341) and sleep disorders(Psychopharmacology, 1990, 100, pp 222-226), ligands of themelatoninergic system have valuable pharmacological properties inrespect of the central nervous system, especially anxiolytic andantipsychotic properties (Neuropharmacology of Pineal Secretions, 1990,8 (3-4), pp 264-272) and analgesic properties (Pharmacopsychiat., 1987,20, pp 222-223), and also for the treatment of Parkinson's disease (J.Neurosurg. 1985, 63, pp 321-341) and Alzheimer's disease (BrainResearch, 1990, 528, pp 170-174). Those compounds have also shownactivity on certain cancers (Melatonin—Clinical Perspectives, OxfordUniversity Press, 1988, pp 164-165), ovulation (Science 1987, 227, pp714-720), diabetes (Clinical Endocrinology, 1986, 24, pp 359-364), andin the treatment of obesity (International Journal of Eating Disorders,1996, 20 (4), pp 443-446).

[0006] Those various effects take place via the intermediary of specificmelatonin receptors. Molecular biology studies have shown the existenceof a number of receptor sub-types that can bind the hormone (TrendsPharmacol. Sci., 1995, 16, p 50; WO 97.04094). It has been possible tolocate some of those receptors and to characterise them for differentspecies, including mammals. In order to be able to understand thephysiological functions of those receptors better, it is very valuableto have specific ligands available. Moreover, by interacting selectivelywith one or other of those receptors, such compounds can be excellentmedicaments for the clinician in the treatment of pathologies associatedwith the melatoninergic system, some of which have been mentioned above.

[0007] In addition to the fact that the compounds of the presentinvention are new, they exhibit very great affinity for melatoninreceptors and/or selectivity for one or other of the melatoninergicreceptor sub-types.

DETAILED DESCRIPTION OF THE INVENTION

[0008] More specifically, the present invention relates to compounds offormula (I):

R-A-R′  (I)

[0009] wherein

[0010] ♦ A represents

[0011] a ring system of formula (II):

[0012] wherein

[0013] X represents an oxygen, sulphur or nitrogen atom or a groupC(H)_(q) (wherein q is 0, 1 or 2) or NR₀ (wherein R₀ represents ahydrogen atom, a linear or branched (C₁-C₆)alkyl group, an aryl group,an aryl-(C₁-C₆)alkyl group in which the alkyl moiety is linear orbranched, or SO₂Ph),

[0014] Y represents a nitrogen atom or a group C(H)_(q) (wherein q is 0,1 or 2),

[0015] Z represents a nitrogen atom or a group C(H)_(q) (wherein q is 0,1 or 2), but X, Y and Z cannot represent three hetero atomssimultaneously,

[0016] B represents a benzene or pyridine nucleus,

[0017] the symbol

means that the bonds may be single or double, it being understood thatthe valency of the atoms is respected.

[0018] wherein R substitutes the ring B and R′ substitutes the ringcontaining the groups X, Y and Z, or R and R′ substitute the ring B,

[0019] a ring system of formula (III):

[0020] wherein

[0021] X′ represents an oxygen or sulphur atom or a group C(H)_(q)(wherein q is 0, 1 or 2),

[0022] Y′ represents a group C(H)_(q) (wherein q is 0, 1 or 2) or NR₀wherein R₀ is as defined hereinbefore,

[0023] Z′ represents a group C(H)_(q) (wherein q is 0, 1 or 2) or NR₀wherein R₀ is as defined hereinbefore,

[0024] T′ represents an oxygen or sulphur atom or a group C(H)_(q)(wherein q is 0, 1 or 2),

[0025] it being understood that, when Y′ or Z′ represents a hetero atom,the other three variables ((X′, Z′, T′) and (X′, Y′, T′), respectively)cannot represent a hetero atom,

[0026] the symbol

is as defined hereinbefore,

[0027] B′ represents:

[0028] a benzene nucleus

[0029] a naphthalene nucleus when X′, Y′, Z′ and T′ do notsimultaneously represent a group C(H)_(q) (wherein q is 0, 1 or 2),

[0030] or a pyridine nucleus when X′ and T′ simultaneously represent agroup C(H)_(q) (wherein q is 0, 1 or 2),

[0031] wherein R substitutes the ring B′ and R′ substitutes the ringcontaining the groups X′, Y′, Z′ and T′, or R and R′ substitute the ringB′,

[0032] a ring system of formula (IV):

[0033] representing the ring systems (IV_(a-d)):

[0034] wherein

[0035] n is an integer such that 0≦n≦3,

[0036] W represents an oxygen, sulphur or nitrogen atom, or a group[C(H)_(q)]_(p) (wherein q is 0, 1 or 2, and p is 1 or 2) or NR₀ whereinR₀ is as defined hereinbefore,

[0037] the symbol

is as defined hereinbefore,

[0038] wherein R′ substitutes the ring

[0039] and R substitutes one or other of the two other rings,

[0040] or a biphenyl group wherein R substitutes one of the benzenerings and R′ substitutes the other, or R and R′ substitute the samebenzene ring,

[0041] it being understood that the ring systems of formulae (II), (III)and (IV) and the biphenyl group may be unsubstituted or substituted (inaddition to the substituents R and R′) by from 1 to 6 radicals, whichmay be the same or different, selected from R_(a), OR_(a), COR_(a),COOR_(a), OCOR_(a), OSO₂CF₃ and halogen atoms,

[0042] wherein R_(a) represents a hydrogen atom, an unsubstituted orsubstituted linear or branched (C₁-C₆)alkyl group, an unsubstituted orsubstituted linear or branched (C₂-C₆)alkenyl group, an unsubstituted orsubstituted linear or branched (C₂-C₆)alkynyl group, a linear orbranched (C₁-C₆)polyhaloalkyl group, an unsubstituted or substituted(C₃-C₈)cycloalkyl group, an unsubstituted or substituted(C₃-C₈)cycloalkyl-(C₁-C₆)alkyl group in which the alkyl group is linearor branched, an unsubstituted or substituted (C₃-C₈)cycloalkenyl group,an unsubstituted or substituted (C₃-C₈)cycloalkenyl-(C₁-C₆)alkyl groupin which the alkyl group is linear or branched, an aryl group, anaryl-(C₁-C₆)alkyl group in which the alkyl moiety is linear or branched,an aryl-(C₁-C₆)alkenyl group in which the alkenyl moiety is linear orbranched, a heteroaryl group, a heteroaryl-(C₁-C₆)alkyl group in whichthe alkyl moiety is linear or branched, a heteroaryl-(C₁-C₆)alkenylgroup in which the alkenyl moiety is linear or branched, anunsubstituted or substituted linear or branched (C₁-C₆)heterocycloalkylgroup, an unsubstituted or substituted heterocycloalkenyl group, asubstituted or unsubstituted heterocycloalkyl-(C₁-C₆)alkyl group inwhich the alkyl moiety is linear or branched, or a substituted orunsubstituted heterocycloalkenyl-(C₁-C₆)alkyl group in which the alkylmoiety is linear or branched,

[0043] ♦ R represents:

[0044] a group of formula (V):

[0045] wherein

[0046] Q represents a sulphur or oxygen atom,

[0047] R′ represents a group NR′_(a)R″_(a) or OR¹ _(a) (wherein R′_(a)and R″_(a), which may be the same or different, may take any of thevalues of R_(a) and may also form, together with the nitrogen atomcarrying them, a 5- to 10-membered cyclic group which may contain, inaddition to the nitrogen atom by which it is linked, from one to threehetero atoms selected from oxygen, sulphur and nitrogen, and R¹ _(a) maytake any of the values of R_(a) except for the hydrogen atom),

[0048] a group of formula (VI):

[0049] wherein

[0050] R² represents a group R_(a) as defined hereinbefore,

[0051] R³ represents a group COR′_(a), CSR′_(a), CONR′_(a)R″_(a),CSNR′_(a)R″_(a), COOR′_(a), CSOR′_(a) or S(O)_(v)R′_(a) (wherein R′_(a)and R″_(a), which may be the same or different, are as definedhereinbefore and may also form, together with the nitrogen atom carryingthem, a cyclic group as defined hereinbefore, and v is 1 or 2),

[0052] a group of formula (VII):

[0053] wherein v is as defined hereinbefore and R⁴ represents a groupNR′_(a)R″_(a), NR_(a)COR′_(a), NR_(a)CSR′_(a), NR_(a)CONR′_(a)R″_(a),NR_(a)CSNR′_(a)R″_(a) or NR_(a)COOR′_(a), wherein R_(a), R′_(a) andR″_(a) are as defined hereinbefore,

[0054] or, when A represents a ring system of formula (II) or (III) or abiphenyl group, forms, together with two adjacent carbon atoms of thering structure A carrying it,

[0055] a ring of formula (VIII):

[0056] the ring formed containing from 5 to 7 atoms and it beingpossible for the said ring to contain from 1 to 3 hetero atoms selectedfrom nitrogen, sulphur and oxygen, and one or more unsaturations, andbeing optionally substituted by one or more radicals, which may be thesame or different, selected from R_(a), OR_(a), COR_(a), COOR_(a),OCOR_(a), NR′_(a)R′_(a), NR_(a)COR′_(a), CONR′_(a)R″_(a), cyano, oxo,SR_(a), S(O)R_(a), SO₂R_(a), CSR_(a), NR_(a)CSR′_(a), CSNR′_(a)R″_(a),NR_(a)CONR′_(a)R″_(a), NR_(a)CSNR′_(a)R″_(a) and halogen atoms,

[0057] wherein R_(a), R′_(a) and R″_(a), which may be the same ordifferent, are as defined hereinbefore and R′_(a) and R″_(a) may alsoform, together with the nitrogen atom carrying them, a cyclic group asdefined hereinbefore,

[0058] ♦ and R′ represents a group of formula (IX):

-G-R⁵   (IX)

[0059] wherein

[0060] G represents an alkylene chain —(CH₂)_(t)— (wherein t is aninteger such that 0≦t≦4 when A represents a tricyclic structure and suchthat 1≦t≦4 when A represents a bicyclic structure), optionallysubstituted by one or more radicals, which may be the same or different,selected from R_(a), OR_(a), COOR_(a), COR_(a) (in which R_(a) is asdefined hereinbefore) or halogen atoms,

[0061] and R⁵ represents a group

[0062] wherein Q, R_(a), R′_(a) and R″_(a) (which may be the same ordifferent) are as defined hereinbefore, it being possible for R′_(a) andR″_(a) to form, together with the nitrogen atom carrying them, a cyclicgroup as defined hereinbefore,

[0063] it being understood that:

[0064] “heterocycloalkyl” is taken to mean any saturated mono- orpoly-cyclic group containing from 5 to 10 atoms containing from 1 to 3hetero atoms selected from nitrogen, oxygen and sulphur,

[0065] “heterocycloalkenyl” is taken to mean any non-aromatic mono- orpoly-cyclic group containing one or more unsaturations, containing from5 to 10 atoms and which may contain from 1 to 3 hetero atoms selectedfrom nitrogen, oxygen and sulphur,

[0066] the term “substituted” used in respect of the expressions“alkyl”, “alkenyl” and “alkynyl” indicates that the groups in questionare substituted by one or more radicals, which may be the same ordifferent, selected from hydroxy, linear or branched (C₁-C₆)alkoxy,linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)polyhaloalkyl, amino and halogen atoms,

[0067] the term “substituted” used in respect of the expressions“cycloalkyl”, “cycloalkylalkyl”, “cycloalkenyl”, “cycloalkenylalkyl”,“heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkylalkyl” and“heterocycloalkenylalkyl” indicates that the cyclic moiety of the groupsin question is substituted by one or more radicals, which may be thesame or different, selected from hydroxy, linear or branched(C₁-C₆)alkoxy, linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)polyhaloalkyl, amino and halogen atoms,

[0068] “aryl” is taken to mean any aromatic, mono- or poly-cyclic groupcontaining from 6 to 22 carbon atoms, and also the biphenyl group,

[0069] “heteroaryl” is taken to mean any aromatic mono- or poly-cyclicgroup containing from 5 to 10 atoms containing from 1 to 3 hetero atomsselected from nitrogen, oxygen and sulphur,

[0070] it being possible for the “aryl” and “heteroaryl” groups to besubstituted by one or more radicals, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, linear orbranched (C₁-C₆)alkyl, linear or branched (C₁-C₆)polyhaloalkyl, cyano,carboxy, nitro, amino and halogen atoms,

[0071] it being understood that:

[0072] when A represents an indole nucleus, there cannot be anysubstituents in the 2-position,

[0073] when A represents an indole nucleus and R represents a group—NHCOR′_(a), —NHCOOR′_(a) or NHCONR′_(a)R″_(a), then G-R⁵ cannotrepresent a group —(CH₂)₂—NHCOR_(b) wherein R_(b) represents a(C₁-C₄)alkyl or CF₃ group,

[0074] when A represents a benzofuran or benzothiophene nucleus, therecannot be any COPh groups (wherein Ph is substituted or unsubstituted)in the 2-position,

[0075] when A represents a benzofuran or benzothiophene nucleus, Rcannot represent a group —NR_(a)COR_(c), —NHSO₂R_(c), —NHCOCH₂R_(c) orNHCONHR_(c) wherein R_(c) represents a heterocyclic or aryl group,

[0076] when A represents a tetrahydronaphthalene group, R⁵ cannotrepresent a group CONR′_(a)R″_(a),

[0077] when A represents a hydrocarbon ring system and R⁵ represents agroup NHCOR′_(a), then R cannot represent a group COOR′_(a),

[0078] the compound of formula (I) cannot represent:

[0079] N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide,

[0080]N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide,

[0081] 8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide,

[0082] their enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.

[0083] Among the pharmaceutically acceptable acids there may mentioned,without implying any limitation, hydrochloric acid, hydrobromic acid,sulphuric acid, phosphonic acid, acetic acid, trifluoroacetic acid,lactic acid, pyruvic acid, malonic acid, succinic acid, glutaric acid,fumaric acid, tartaric acid, maleic acid, citric acid, ascorbic acid,methanesulphonic acid, camphoric acid, oxalic acid etc.

[0084] Among the pharmaceutically acceptable bases there may mentioned,without implying any limitation, sodium hydroxide, potassium hydroxide,triethylamine, tert-butylamine etc.

[0085] Preferred compounds of the invention are those wherein Arepresents a ring system of formula (II′):

[0086] wherein B, X and the symbol

are as defined hereinbefore, or (III′):

[0087] wherein B′, T′, X′ and the symbol

are as defined hereinbefore.

[0088] The invention advantageously relates to compounds wherein A(unsubstituted or substituted by a single substituent (in addition to Rand R′) preferably in the 2-position (formula II′) or in the 3-position(formula III′), represents a cyclic system of formula (II′):

[0089] wherein B, X and the symbol

are as defined hereinbefore, such as, for example,(dihydro)benzothiophene, (dihydro)benzofuran, indole, indoline, indan,indene, azaindole, thienopyridine or furopyridine, or of formula (III′):

[0090] wherein B′, T′, X′ and the symbol

are as defined hereinbefore, such as, for example, naphthalene,tetrahydronaphthalene, (thio)chroman, (dihydro)benzodioxin,(dihydro)benzoxathiin, (dihydro)benzochromene.

[0091] Even more advantageously, the invention relates to compoundswherein A of formula (II′) or (III′) is substituted by R in the5-position (formula II′) or 7-position (formula III′) and by R′ in the3-position (formula II′) or I - or 2-position (formula III′).

[0092] Preferred substituents R of the invention are those representedby a group of formula (V), (VI) or (VII).

[0093] More advantageously, preferred substituents R of the inventionare those represented by a group of formula (V) wherein Q represents anoxygen atom and R¹ represents a group NR′_(a)R″_(a) (wherein R′_(a) andR″_(a) are as defined hereinbefore) or OR¹ _(a) (wherein R¹ _(a) is asdefined hereinbefore),

[0094] a group of formula (VI) wherein R³ represents a group COR′_(a) orCOOR′_(a) (wherein R′_(a) is as defined hereinbefore),

[0095] or a group of formula (VII) wherein v is 2 and R⁴ represents agroup NR′_(a)R″_(a) as defined hereinbefore.

[0096] Even more advantageously, preferred substituents R of theinvention are those represented by a group CONR′_(a)R″_(a) orSO₂NR′_(a)R″_(a) wherein R′_(a) and R″_(a), which may be the same ordifferent, represent a hydrogen atom or an alkyl, polyhaloalkyl,alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkylalkyl,cycloalkenylalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group,such as, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl,allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or form, together with the nitrogen atom carrying them, a piperazine,piperidine, morpholine or thiomorpholine group, or by a group NCOR′_(a),NCOOR′_(a) or COOR¹ _(a) wherein R′_(a) represents a hydrogen atom, analkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,and R¹ _(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, aryl, arylalkyl, heteroaryl or heteroarylalkyl group, suchas, for example, methyl, ethyl, propyl, isopropyl, butyl, isobutyl,sec-butyl, tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl,allyl, propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.

[0097] Preferred substituents R′ of the invention are those wherein Grepresents an unsubstituted or substituted alkylene chain —(CH₂)_(t)—,wherein t is 2 or 3, and R⁵ represents a group

[0098] wherein R_(a), R′_(a), R″_(a) and Q are as defined hereinbefore.

[0099] Even more advantageously, preferred substituents R′ of theinvention are those wherein G represents a group —(CH₂)_(t)—, wherein tis 2 or 3, and R⁵ represents a group

[0100] wherein R′_(a) represents an alkyl, polyhaloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or G represents a group —(CH₂)₃— and R⁵ represents a group

[0101] wherein R_(a) represents an alkyl, polyhaloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.

[0102] More especially, preferred compounds of the invention are thosewherein A represents a ring system of formula (II′) or (III′) and Rrepresents a group of formula (V), (VI) or (VII).

[0103] More advantageously, the invention relates to compounds wherein:

[0104] A represents a group of formula (II′) or (III′) substituted inthe 5-position (formula II′) or 7-position (formula III′) by R and inthe 3-position (formula II′) or 1- or 2-position (formula III′) by R′,

[0105] and R represents a group CONR′_(a)R″_(a), SO₂NR′_(a)R″_(a), COOR¹_(a), NHCOR′_(a) or NHCOOR′_(a) (wherein R′_(a), R′_(a) and R′_(a) areas defined hereinbefore).

[0106] Even more advantageously, preferred compounds of the inventionare those wherein A represents a ring system of formula (II′) or (III′)optionally substituted (in addition to R and R′) by a substituent in the2-position (formula II′) or 3-position (formula III′),

[0107] substituted in the 5-position (formula II′) or 7-position(formula III′) by R and in the 3-position (formula II′) or 1- or2-position (formula III′) by R′,

[0108] R represents a group CONR′_(a)R″_(a), SO₂NR′_(a)R″_(a),COOR′_(a), NHCOR′_(a) or NHCOOR′_(a) (wherein R′_(a), R″_(a) and R¹ _(a)are as defined hereinbefore),

[0109] and R′ is such that G represents an unsubstituted or substitutedalkylene chain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents agroup

[0110] wherein R_(a), R′_(a), R″_(a) and Q are as defined hereinbefore.

[0111] Even more especially, the invention relates to(dihydro)benzothiophenes, (dihydro)benzofurans, indoles, indolines,indenes, indans, azaindoles, thieno- or furopyridines optionallysubstituted in the 2-position, and to dihydronaphthalenes,tetrahydronaphthalenes, naphthalenes or chromans optionally substitutedin the 3-position,

[0112] substituted in the 5-position (or 7-position, respectively) by agroup CONR′_(a)R″_(a), SO₂NR′_(a)R″_(a), COOR′_(a), NHCOR′_(a) orNHCOOR′_(a) wherein R′_(a) and R′_(a), which may be the same ordifferent, represent a hydrogen atom, an alkyl, polyhaloalkyl, alkenyl,alkynyl, cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl,aryl, arylalkyl, heteroaryl or heteroarylalkyl group, such as, forexample, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,or R′_(a) and R″_(a) form, together with the nitrogen atom carryingthem, a piperazine, piperidine, morpholine or thiomorpholine group, andR¹ _(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl,cycloalkyl, cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl,arylalkyl, heteroaryl or heteroarylalkyl group, such as, for example,methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl,tert-butyl, pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl,propargyl, phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl,

[0113] and substituted in the 3-position (or 1- or 2-position,respectively) by a group —(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 andR′_(a) represents an alkyl, polyhaloalkyl, alkenyl, alkynyl, cycloalkyl,cycloalkenyl, cycloakylalkyl, cycloalkenylalkyl, aryl, arylalkyl,heteroaryl or heteroarylalkyl group, such as, for example, methyl,ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl,pentyl, isopentyl, hexyl, trifluoromethyl, vinyl, allyl, propargyl,phenyl, naphthyl, benzyl, phenethyl, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cyclohexenyl, methylcyclopropyl,ethylcyclopropyl, furyl, thienyl, pyridyl, furylmethyl, pyridylmethyl.

[0114] Even more advantageously, preferred compounds of the inventionare:

[0115] naphthalenes, dihydronaphthalenes or tetrahydronaphthalenesoptionally substituted in the 3-postion, substituted in the 7-positionby a group NHCOR_(a), NHCOOR_(a), CONHR_(a) or COOR¹ _(a) (wherein R_(a)and R¹ _(a) are as defined hereinbefore) and substituted in the1-position by a group —(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 andR′_(a) is as defined hereinbefore,

[0116] or benzofurans or benzothiophenes optionally substituted in the2-position, substituted in the 5-postion by a group NHCOR_(a),NHCOOR_(a), CONHR_(a) or COOR¹ _(a) (wherein R_(a) and R¹ _(a) are asdefined hereinbefore) and substituted in the 3-position by a group—(CH₂)_(t)—NHCOR′_(a) wherein t is 2 or 3 and R′_(a) is as definedhereinbefore.

[0117] The invention relates very particularly to the compounds offormula (I) that are

[0118] N-{2-[6-(acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide,

[0119] methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate,

[0120] methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,

[0121] methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,

[0122] methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate,

[0123]N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide,

[0124] 3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide,

[0125]3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide,

[0126] 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide,

[0127]3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,

[0128] 3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,

[0129]3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,

[0130] 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,

[0131]3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,

[0132] 3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,

[0133]3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,

[0134]N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene-5-carboxamide,

[0135]N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide,

[0136]N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide,

[0137] N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide,

[0138] N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide,

[0139]N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide,

[0140] N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide,

[0141] N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide,

[0142] N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,

[0143]N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,

[0144]N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,

[0145] N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide,

[0146] N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide,

[0147] N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,

[0148] N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,

[0149] N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,

[0150] N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide,

[0151]N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropanecarboxamide,

[0152]N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide,

[0153]N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide,

[0154]N-(2-{5-[(cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)benzamide,

[0155]N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide,

[0156]N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarboxamide,

[0157]N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide,

[0158]N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropane-carboxamide,

[0159]N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide,

[0160]N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)cyclopropane-carboxamide,

[0161]N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)benzamide,

[0162]N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamide,

[0163] methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate,

[0164] methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,

[0165] tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate,

[0166] tert-butyl3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate,

[0167] methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate,

[0168] methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate,

[0169] methyl5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate,

[0170] methyl3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate,

[0171] ethyl3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate,

[0172] methyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,

[0173] methyl3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,

[0174] methyl3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,

[0175] methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,

[0176] ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate,

[0177] methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate,

[0178] hexylN-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate,

[0179] methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate,

[0180] methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate,

[0181] methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,

[0182] methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate,

[0183] methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate,

[0184] 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide.

[0185] The enantiomers and diastereoisomers, as well as the additionsalts with a pharmaceutically acceptable acid or base, of the preferredcompounds of the invention form an integral part of the invention.

[0186] The invention relates also to a process for the preparation ofcompounds of formula (I), which process is characterised in that thereis used as starting material the compound of formula (X)

[0187] wherein A and R′ are as defined hereinbefore, which is subjectedto demethylation using conventional agents such as HBr, AlCl₃, AlBr₃,BBr₃ or Lewis acid/nucleophile binary systems such as AlCl₃/PhCH₂SH, orBBr₃/Me₂S, for example, to obtain the compound of formula (XI):

HO-A-R′  (XI)

[0188] wherein A and R′ are as defined hereinbefore,

[0189] ♦ which is converted, by means of the action of reagents such asPOCl₃, PCl₅, Ph₃PBr₂, PhPCl₄, HBr or HI, into the correspondinghalogenated compound of formula (XII):

Hal-A-R′  (XII)

[0190] wherein A and R′ are as defined hereinbefore and Hal represents ahalogen atom (which compounds of formula (XII) can be obtained byexchange reactions such as, for example, the treatment of a chlorinatedcompound with KF in dimethylformamide to yield the correspondingfluorinated compound or the treatment of a brominated compound with KIin the presence of copper salts to yield the corresponding iodinatedcompound),

[0191] which is treated:

[0192] with carbon monoxide and Bu₃SnH, the reaction being catalysedwith palladium(0), to yield the corresponding aldehyde of formula(XIII):

[0193] wherein A and R′ are as defined hereinbefore,

[0194] which compound of formula (XIII) may alternatively be obtained bycustomary lithiation methods starting from the halogenated compound offormula (XII), or via the corresponding vinyl compound (obtainedstarting from the compound of formula (XII) by the action ofvinyltributyltin and tetrakis palladium) subjected to ozonolysis, orfurthermore by direct formylation of the nucleus A, for exampleaccording to a Vilsmeier reaction,

[0195] which compound of formula (XIII) is subjected to an oxidisingagent to obtain the compound of formula (XIV):

HOOC-A-R′  (XIV)

[0196] wherein A and R′ are as defined hereinbefore, which is:

[0197] either subjected, in the presence of an acid catalyst, to theaction of an alcohol of formula R¹ _(a)OH, wherein R¹ _(a) is as definedhereinbefore, to yield the compound of formula (I/a), a particular caseof the compounds of formula (I):

[0198] wherein A, R¹ _(a) and R′ are as defined hereinbefore,

[0199] which may be subjected to a thionating agent, such as Lawesson'sreagent, for example, to yield the compound of formula (I/b), aparticular case of the compounds of formula (I):

[0200] wherein A, R¹ _(a) and R′ are as defined hereinbefore,

[0201] or converted, after the action of thionyl chloride and an azide,and then of an acid, into the compound of formula (XV):

H₂N-A-R′  (XV)

[0202] wherein A and R′ are as defined hereinbefore, with which there iscondensed:

[0203] either an acyl chloride ClCOR_(a) or the corresponding anhydride(mixed or symmetrical), wherein R_(a) is as defined hereinbefore, toyield the compound of formula (I/c), a particular case of the compoundsof formula (I):

[0204] wherein R_(a), A and R′ are as defined hereinbefore,

[0205] which may be subjected to the action of a compound of formula(XVI):

R¹ _(a)-J   (XVI)

[0206] wherein R¹ _(a) is as defined hereinbefore and J represents aleaving group such as a halogen atom or a tosyl group,

[0207] to obtain the compound of formula (I/d), a particular case of thecompounds of formula (I):

[0208] wherein R_(a), R¹ _(a), A and R′ are as defined hereinbefore,

[0209] which compounds of formulae (I/c) and (I/d) constitute thecompound of formula (I/e), a particular case of the compounds of formula(I):

[0210] wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,

[0211] which compound of formula (I/e) may be subjected to a thionatingagent, such as Lawesson's reagent, for example, to obtain the compoundof formula (I/f), a particular case of the compounds of formula (I):

[0212] wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,

[0213] or a compound of formula (XVII):

Q=C═N—R′_(a)   (XVII)

[0214] wherein Q and R′_(a) are as defined hereinbefore,

[0215] to yield the compound of formula (I/g), a particular case of thecompounds of formula (I):

[0216] wherein R′_(a), Q, A and R′ are as defined hereinbefore,

[0217] which may be subjected to the action of a compound of formula(XVI) to obtain the compound of formula (I/h), a particular case of thecompounds of formula (I):

[0218] wherein Q, R¹ _(a), A and R′ are as defined hereinbefore and R²_(a) and R′² _(a), which may be the same or different, may take any ofthe values of R_(a) except for the hydrogen atom and cannot form acyclic structure together with the nitrogen atom carrying them,

[0219] or a compound of formula (XVIII):

[0220] wherein R′_(a) is as defined hereinbefore, or its correspondinganhydride (R′_(a)OCO)₂O,

[0221] to obtain the compound of formula (I/i), a particular case of thecompounds of formula (I):

[0222] wherein R′_(a), A et R′ are as defined hereinbefore,

[0223] which may be subjected to the action of a compound of formula(XVI) and/or the action of a thionating agent to yield the compound offormula (I/j), a particular case of the compounds of formula (I):

[0224] wherein R_(a), R′_(a), Q, A and R′ are as defined hereinbefore,

[0225] or a compound of formula (XIX):

R_(a)SO₂Cl   (XIX)

[0226] wherein R_(a) is as defined hereinbefore,

[0227] optionally followed by the action of a compound of formula (XVI)to yield the compound of formula (I/k), a particular case of thecompounds of formula (I):

[0228] wherein R_(a), A and R′ are as defined hereinbefore,

[0229] ♦ or which compound of formula (XI) is converted, by means of theaction of benzylthiol and trifluoromethanesulphonic acid, into thecorresponding benzylthio compound of formula (XX):

Ph-CH₂—S-A-R′  (XX)

[0230] wherein A and R′ are as defined hereinbefore,

[0231] which is placed in the presence of iodosobenzene and hydrochloricacid to yield the compound of formula (XXI):

ClSO₂-A-R′  (XXI)

[0232] wherein A and R′ are as defined hereinbefore, with which there iscondensed an amine R′_(a)R″_(a)NH (wherein R′_(a) and R″_(a) are asdefined hereinbefore),

[0233] to obtain the compound of formula (I/l), a particular case of thecompounds of formula (I):

R′_(a)R″_(a)NSO₂-A-R′  (I/l)

[0234] wherein R′_(a), R″_(a), A and R′ are as defined hereinbefore,

[0235] it being possible for the compound of formula (I/la), aparticular case of the compounds of formula (I/l):

H₂NSO₂-A-R′  (I/la)

[0236] wherein A and R′ are as defined hereinbefore, to be subjected tothe action

[0237] of an acyl chloride ClCOR′_(a), optionally followed by the actionof a compound of formula (XVI) and/or Lawesson's reagent,

[0238] to yield the compound of formula (I/m), a particular case of thecompounds of formula (I):

[0239] wherein R_(a), R′_(a), Q, A and R′ are as defined hereinbefore,

[0240] of a compound of formula (XVII), optionally followed by theaction of a compound of formula (XVI) to obtain the compound of formula(I/n), a particular case of the compounds of formula (I):

[0241] wherein R_(a), R′_(a), R″_(a), Q, A and R′ are as definedhereinbefore,

[0242] or of a compound of formula (XVIII), optionally followed by theaction of a compound of formula (XVI),

[0243] to yield the compound of formula (I/o), a particular case of thecompounds of formula (I):

[0244] wherein R_(a), R′_(a), A and R′ are as defined hereinbefore,

[0245] which compounds (I/a) to (I/o) can be purified in accordance witha conventional separation technique, are converted, if desired, intotheir addition salts with a pharmaceutically acceptable acid or baseand, optionally, are separated into their isomers in accordance with aconventional separation technique.

[0246] The starting compounds (X) are either commercially available orare described in the literature, for example in the Patent ApplicationsEP0447285, EP0527687, EP0562956, EP0591057, EP0662471, EP0745586,EP0709371, EP0745583, EP0721938, EP0745584, EP0737670, EP0737685, orW09738682.

[0247] Another advantageous process of the invention relating topreparation of the compounds of formula (I) is characterised in thatthere is used as starting material the compound of formula (XXII):

[0248] wherein R and the symbol

are as defined hereinbefore, Y″ represents a group C(H)_(q) (wherein qis 0, 1 or 2) or a bond, and X″ represents an oxygen, nitrogen orsulphur atom or a group C(H)_(q) (wherein q is 0, 1 or 2) or NR₀(wherein R₀ is as defined hereinbefore), it being understood that whenX″ represents a nitrogen atom or a group NR₀ then Y″ represents a bond,

[0249] which is subjected to a Wittig reaction and then to reduction toyield the compound of formula (XXIII):

[0250] wherein R, X″, Y″, G and the symbol

are as defined hereinbefore,

[0251] which may be oxidised to yield the compound of formula (XXIV):

[0252] wherein R¹, X″, Y″, G and the symbol

are as defined hereinbefore,

[0253] which is:

[0254] either hydrolysed in an acid or basic medium and then subjected,after activation to the acid chloride form or in the presence of acoupling agent, to the action of an amine HNR′_(a)R″_(a) wherein R′_(a)and R″_(a) are as defined hereinbefore to yield the compound of formula(I/p), a particular case of the compounds of formula (I):

[0255] wherein R, X″, Y″, G, R′_(a), R″_(a) and the symbol

are as defined hereinbefore,

[0256] which may be subjected to a thionating agent such as Lawesson'sreagent to yield the compound of formula (I/q), a particular case of thecompounds of formula (I):

[0257] wherein R, X″, Y″, G, R′_(a), R″_(a) and the symbol

are as defined hereinbefore,

[0258] or hydrolysed in an acid or basic medium and then converted intothe corresponding azide to yield, after having been subjected to aCurtius rearrangement and hydrolysis, the compound of formula (XXV):

[0259] wherein R, X″, Y″and G are as defined hereinbefore,

[0260] which is reacted with

[0261] an acyl chloride ClCOR′_(a) or the corresponding anhydride (mixedor symmetrical) wherein R′_(a) is as defined hereinbefore, optionallyfollowed by the action of a compound of formula (XVI) and/or the actionof a thionating agent to yield the compound of formula (I/r), aparticular case of the compounds of formula (I):

[0262] wherein R. X″, Y″, G, R_(a), R′_(a), Q and the symbol

are as defined hereinbefore,

[0263] or with a compound of formula (XVII), optionally followed by theaction of a compound of formula (XVI) to yield the compound of formula(I/s), a particular case of the compounds of formula (I):

[0264] wherein R, X″, Y″, G, R_(a), R′_(a), R″_(a), Q and the symbol

are as defined hereinbefore,

[0265] which compounds (I/p) to (I/s) can be purified in accordance witha conventional separation technique, are converted, if desired, intotheir addition salts with a pharmaceutically acceptable acid or baseand, optionally, are separated into their isomers in accordance with aconventional separation technique.

[0266] The compounds of formula (XXII) are either commercially availableor easily accessible to the person skilled in the art,

[0267] starting from the compound of formula (XXVI):

[0268] wherein R is as defined hereinbefore and X′″ represents an oxygenor sulphur atom or a group NR₀ (wherein R₀ is as defined hereinbefore),

[0269] (the compound of formula (XXVI) either being commerciallyavailable or being obtained starting from the compound of formula(XXVI′):

[0270] wherein X′″ is as defined hereinbefore, by conventional reactionsfor substitution of the aromatic nucleus),

[0271] which is subjected to the action of AlCl₃ to yield the compoundof formula (XXVII):

[0272] wherein R and X′″ are as defined hereinbefore,

[0273] which is subjected to bromination to obtain the compound offormula (XXVIII):

[0274] wherein X′″ and R are as defined hereinbefore,

[0275] which is placed in a basic medium to yield the compound offormula (XXIX), a particular case of the compounds of formula (XXII):

[0276] wherein R and X′″ are as defined hereinbefore,

[0277] or starting from the compound of formula (XXX):

[0278] wherein R, X″, Y″ and the symbol

are as defined hereinbefore,

[0279] which is cyclised in the presence of polyphosphoric acid to yieldthe compound of formula (XXII).

[0280] The invention relates also to a process for the preparation ofcompounds of formula (I) wherein R represents a ring of formula (VIII),which process is characterised in that compounds of formulae (I/a) to(I/s) are used as starting materials, which are cyclised according tomethods described in the literature, for example in the PatentApplications EP0708099 or W09732871.

[0281] The compounds of the invention and pharmaceutical compositionscomprising them are proving to be useful in the treatment of disordersof the melatoninergic system.

[0282] Pharmacological study of the compounds of the invention has infact shown them to be non-toxic, to have strong affinity for melatoninreceptors and to possess important activities in respect of the centralnervous system and, in particular, there have been found therapeuticproperties in relation to sleep disorders, anxiolytic, antipsychotic andanalgesic properties and in relation to the microcirculation, enablingit to be established that the products of the invention are useful inthe treatment of stress, sleep disorders, anxiety, seasonal affectivedisorder, cardiovascular pathologies, pathologies of the digestivesystem, insomnia and fatigue resulting from jet lag, schizophrenia,panic attacks, melancholia, appetite disorders, obesity, insomnia,psychotic disorders, epilepsy, diabetes, Parkinson's disease, seniledementia, various disorders associated with normal or pathologicalageing, migraine, memory loss, Alzheimer's disease, and also cerebralcirculation disorders. In another field of activity, it appears that, intreatment, the products of the invention can be used in sexualdysfunction, that they have ovulation-inhibiting properties andimmunomodulating properties and are able to be used in the treatment ofcancers.

[0283] The compounds will preferably be used in the treatment ofseasonal affective disorder, sleep disorders, cardiovascularpathologies, insomnia and fatigue resulting from jet lag, appetitedisorders and obesity.

[0284] For example, the compounds will be used in the treatment ofseasonal affective disorder and sleep disorders.

[0285] The present invention relates also to pharmaceutical compositionscomprising at least one compound of formula (I), alone or in combinationwith one or more pharmaceutically acceptable excipients.

[0286] Among the pharmaceutical compositions according to the inventionthere may be mentioned more especially those that are suitable for oral,parenteral, nasal, per- or trans-cutaneous, rectal, perlingual, ocularor respiratory administration and especially tablets, dragees,sublingual tablets, sachets, paquets, gelatin capsules, glossettes,lozenges, suppositories, creams, ointments, dermal gels and drinkable orinjectable ampoules.

[0287] The dosage varies according to the sex, age and weight of thepatient, the route of administration, the nature of the therapeuticindication, or possible associated treatments, and ranges from 0.01 mgto 1 g per 24 hours in 1 or more administrations.

[0288] The following Examples illustrate the invention but do not limitit in any way. The following Preparations yield compounds of theinvention or synthesis intermediates that are useful in preparation ofthe compounds of the invention.

[0289] Preparation 1: N-[2-(7-Hydroxy-1-naphthyl)ethyl]acetamide

[0290] Under an inert atmosphere, 27.5 mmol of boron tribromide/dimethylsulphide complex are dissolved in 100 ml of dichloromethane and stirredfor 15 min at ambient temperature. A solution of 13.7 mmol ofN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide in 50 ml of dichloromethaneis added and the reaction mixture is heated at reflux for 30 hours.After cooling, the reaction mixture is hydrolysed with caution and thedichloromethane is evaporated off. The mixture is then extracted withethyl acetate, the combined organic phases are washed with a 1M aqueoussolution of potassium bicarbonate and then with 1M sodium hydroxidesolution. The organic phase is dried over magnesium sulphate andconcentrated to yield the title compound.

[0291] Preparation 2:N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-phenylacetamide

[0292] The procedure is as in Preparation 1, but theN-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced byN-[2-(7-methoxy-1-naphthyl)ethyl]-2-phenylacetamide.

[0293] In Preparations 3 to 37, the procedure is as in Preparation 1,but the N-[2-(7-methoxy-1-naphthyl)ethyl]acetamide is replaced by theappropriate methoxylated starting substrate.

[0294] Preparation 3: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-bromoacetamide

[0295] Preparation 4:N-[2-(8-Hexyl-7-hydroxy-1-naphthyl)ethyl]-2-phenylacetamide

[0296] Preparation 5:N-Cyclopropylmethyl-2-(7-hydroxy-1-naphthyl)acetamide

[0297] Preparation 6: N-Cyclohexyl-4-(7-hydroxy-1-naphthyl)butanamide

[0298] Preparation 7:N-[2-(7-Hydroxy-1-naphthyl)ethyl]-N-methyl-N′-propylurea

[0299] Preparation 8: N-[3-(7-Hydroxy-1-naphthyl)propyl]acetamide

[0300] Preparation 9: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-3-butenamide

[0301] Preparation 10:N-[3-(7-Hydroxy-1-naphthyl)propyl]-1-cyclohexanecarboxamide

[0302] Preparation 11:N-[2-(2-Hydroxy-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide

[0303] Preparation 12:N-[2-(2-Hydroxy-1-naphthyl)-1-methylethyl]propanamide

[0304] Preparation 13:N-[2-(7-Hydroxy-3-phenyl-1-naphthyl)ethyl]acetamide

[0305] Preparation 14:N-[2-(3-Benzoyl-7-hydroxy-1-naphthyl)ethyl]-N′-propylurea

[0306] Preparation 15:N-{2-13-(Cyclopropylmethyl)-7-hydroxy-1-naphthyl]ethyl}acetamide

[0307] Preparation 16:N-[3-(5-Hydroxybenzo[b]furan-3-yl)propyl]acetamide

[0308] Preparation 17:N-Methyl-4-(5-hydroxybenzo[b]furan-3-yl)butanamide

[0309] Preparation 18: N-[2-(5-Hydroxybenzo[b]furan-3-yl)ethyl]acetamide

[0310] Preparation 19:N-[(2-Benzyl-5-hydroxybenzo[b]thiophen-3-yl)methyl]acetamide

[0311] Preparation 20:N-[2-(5-Hydroxythieno[3,2-b]pyridin-3-yl)ethyl]acetamide

[0312] Preparation 21: N-[2-(5-Hydroxy-1H-3-indolyl)ethyl]benzamide

[0313] Preparation 22:N-{2-[2-(4-Fluorobenzyl)-5-hydroxy-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}acetamide

[0314] Preparation 23:N-[2-(2-Benzyl-5-hydroxybenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

[0315] Preparation 24:N-[(6-Hydroxy-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

[0316] Preparation 25:N-[2-(6-Hydroxy-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide

[0317] Preparation 26:N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]acetamide

[0318] Preparation 27:N-[(6-Hydroxy-2-phenyl-2H-3-chromenyl)methyl]butanamide

[0319] Preparation 28:N-[2-(6-Hydroxy-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide

[0320] Preparation 29:N-[2-(7-Hydroxy-1,4-benzodioxin-2-yl)ethyl-N′-propylurea

[0321] Preparation 30:N-[2-(7-Hydroxy-2,3-dihydro-1,4-benzodioxin-2-yl)ethyl]acetamide

[0322] Preparation 31:N-[2-(6-Hydroxy-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

[0323] Preparation 32:N-[(9-Hydroxy-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylacetamide

[0324] Preparation 33:N-Cyclopropyl-N′-(4-hydroxy-2,3-dihydro-1H-2-phenalenyl)thiourea

[0325] Preparation 34: N-Cyclobutyl-3-hydroxy-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

[0326] Preparation 35:N-{2-[7-Hydroxy-3-naphthyl-1-naphthyl]ethyl}heptanamide

[0327] Preparation 36:N-[2-(7-Hydroxy-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

[0328] Preparation 37:N-[2-(6-Hydroxy-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

[0329] Preparation 38: N-Cyclohexyl-4-(7-chloro-1-naphthyl)butanamide

[0330] Chlorine (10 mmol) is bubbled into dichlorophenylphosphine at aflow rate such that the reaction temperature is maintained between 70and 80° C. After all the chlorine has been added, the phenylphosphinetetrachloride so obtained is a pale yellow liquid. 10 mmol of theproduct obtained in Preparation 5 are added all at once and the reactionmixture is heated at 160° C. overnight. After cooling, the solution ispoured into a water/ice mixture (20 ml) and is neutralised with a 50 %aqueous solution of sodium hydroxide. After extraction with ether, theorganic phases are dried and concentrated under reduced pressure toyield a residue, which is chromatographed on silica gel to obtain thepure title product.

[0331] In Preparation 39, the procedure is as in Preparation 38, but theappropriate starting compound is used.

[0332] Preparation 39:N-[(6-Chloro-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

[0333] Starting compound: Preparation 24

[0334] Preparation 40: N-[2-(7-Bromo-1-naphthyl)ethyl]-2-phenylacetamide

[0335] Triphenylphosphine (10 mmol) and acetonitrile (70 ml) are pouredinto a 150 ml three-necked flask equipped with a bromine funnel, acondenser surmounted by a tube filled with calcium chloride and amechanical stirrer. The solution is cooled with the aid of an ice bath,with stirring, and bromine is added (10 mmol). At the end of theaddition, the ice bath is removed and the product obtained inPreparation 2 (8 mmol) is then added. The reaction mixture is stirred at60-70° C. until the starting compound has disappeared (monitored byTLC). At the end of the reaction, the mixture is filtered and thefiltrate is then concentrated under reduced pressure. The residue istaken up in ethyl acetate, washed with water and then with saturatedpotassium hydrogen carbonate solution and once again with water, and isthen dried over magnesium sulphate and concentrated under reducedpressure. The residue is filtered through silica gel to yield the titleproduct.

[0336] In Preparations 41 to 72.1, the procedure is as in Preparation40, starting from the appropriate reactant.

[0337] Preparation 41:N-Cyclopropylmethyl-2-(7-bromo-1-naphthyl)acetamide

[0338] Starting compound: Preparation 5

[0339] Preparation 42:N-[2-(7-Bromo-1-naphthyl)ethyl]-N-methyl-N′-propylurea

[0340] Starting compound: Preparation 7

[0341] Preparation 43:N-[3-(7-Bromo-1-naphthyl)propyl]-1-cyclohexanecarboxamide

[0342] Starting compound: Preparation 10

[0343] Preparation 44:N-[2-(2-Bromo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide

[0344] Starting compound: Preparation 11

[0345] Preparation 45:N-[2-(3-Benzoyl-7-bromo-1-naphthyl)ethyl]-N′-propylurea

[0346] Starting compound: Preparation 14

[0347] Preparation 46: N-[3-(5-Bromobenzo[b]furan-3-yl)propyl]acetamide

[0348] Starting compound: Preparation 16

[0349] Preparation 47:N-[(2-Benzyl-5-bromobenzo[b]thiophen-3-yI)methyl]acetamide

[0350] Starting compound: Preparation 19

[0351] Preparation 48:N-[2-(5-Bromo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3yl)ethyl]acetamide

[0352] Starting compound: Preparation 22

[0353] Preparation 49:N-[2-(6-Bromo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide

[0354] Starting compound: Preparation 25

[0355] Preparation 50:N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]acetamide

[0356] Starting compound: Preparation 26

[0357] Preparation 51:N-[2-(6-Bromo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide

[0358] Starting compound: Preparation 28

[0359] Preparation 52:N-[2-(7-Bromo-1,4-benzodioxin-2-yl)ethyl]-N′-propylurea

[0360] Starting compound: Preparation 29

[0361] Preparation 53:N-[2-(6-Bromo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

[0362] Starting compound: Preparation 31

[0363] Preparation 54:N-[(9-Bromo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropylacetamide

[0364] Starting compound: Preparation 32

[0365] Preparation 55:N-(4-Bromo-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

[0366] Starting compound: Preparation 33

[0367] Preparation 56: N-Cyclobutyl-6-bromo-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

[0368] Starting compound: Preparation 34

[0369] Preparation 57:N-[2-(7-Bromo-3-naphthyl-1-naphthyl)ethyl]heptanamide

[0370] Starting compound: Preparation 35

[0371] Preparation 58: N-[2-(7-Bromo-1-naphthyl)ethyl]acetamide

[0372] Starting compound: Preparation 1

[0373] Preparation 59: N-[2-(7-Bromo-1-naphthyl)ethyl]-3-butenamide

[0374] Starting compound: Preparation 9

[0375] Preparation 60: N-[2-(7-Bromo-1-naphthyl)ethyl]-2-bromoacetamide

[0376] Starting compound: Preparation 3

[0377] Preparation 61:N-[2-(7-Bromo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

[0378] Starting compound: Preparation 4

[0379] Preparation 62: N-[3-(7-Bromo-1-naphthyl)propyl]acetamide

[0380] Starting compound: Preparation 8

[0381] Preparation 63:N-[2-(2-Bromo-1-naphthyl)-1-methylethyl]propanamide

[0382] Starting compound: Preparation 12

[0383] Preparation 64:N-{2-[7-Bromo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

[0384] Starting compound: Preparation 15

[0385] Preparation 65: N-Methyl-3-(5-bromobenzo[b]furan-3-yl)butanamide

[0386] Starting compound: Preparation 17

[0387] Preparation 66:N-[2-(5-Bromothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

[0388] Starting compound: Preparation 20

[0389] Preparation 67: N-[2-(5-Bromo-1H-3-indolyl)ethyl]benzamide

[0390] Starting compound: Preparation 21

[0391] Preparation 68:N-[2-(2-Benzyl-5-bromobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

[0392] Starting compound: Preparation 23

[0393] Preparation 69:N-[(6-Bromo-2-phenyl-2H-3-chromenyl)methyl]butanamide

[0394] Starting compound: Preparation 27

[0395] Preparation 70:N-[2-(6-Bromo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

[0396] Starting compound: Preparation 37

[0397] Preparation 71: N-[2-(7-Bromo-3-phenyl-1-naphthyl)ethyl]acetamide

[0398] Starting compound: Preparation 13

[0399] Preparation 72: N-[2-(5-Bromobenzo[b]furan-3-yl)ethyl]acetamide

[0400] Starting compound: Preparation 18

[0401] Preparation 72.1:N-[2-7-Bromo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

[0402] Starting compound: Preparation 36

[0403] Preparation 73: N-[2-(7-Iodo-1-naphthyl)ethyl]-2-phenylacetamide

[0404] A mixture of the product obtained in Preparation 40 (2 mmol),potassium iodide (30 mmol) and copper(I) iodide (10 mmol) inhexamethylphosphoramide (6 ml) is heated at 150-160° C., with stirring,under a nitrogen atmosphere until 90% conversion has been achieved(monitored by TLC). Then, dilute hydrochloric acid, and then ether, areadded and the mixture is then filtered to remove the insoluble copper(I)salts. The organic phase is separated off, washed with sodium sulphitesolution and with water, dried over magnesium sulphate and evaporated toyield a residue which is chromatographed on silica gel to yield thetitle product.

[0405] In Preparations 74 to 108 the procedure is as in Preparation 73,but the product of Preparation 40 is replaced by the appropriatesubstrate.

[0406] Preparation 74:N-Cyclopropylmethyl-2-(7-iodo-1-naphthyl)acetamide

[0407] Starting compound: Preparation 41

[0408] Preparation 75:N-[2-(7-Iodo-1-naphthyl)ethyl]-N-methyl-N′-propylurea

[0409] Starting compound: Preparation 42

[0410] Preparation 76:N-[3-(7-Iodo-1-naphthyl)propyl]-1-cyclohexanecarboxamide

[0411] Starting compound: Preparation 43

[0412] Preparation 77:N-[2-(2-Iodo-1-naphthyl)ethyl]-2,2,2-trifluoroacetamide

[0413] Starting compound: Preparation 44

[0414] Preparation 78:N-[2-(3-Benzoyl-7-iodo-1-naphthyl)ethyl]-N′-propylurea

[0415] Starting compound: Preparation 45

[0416] Preparation 79: N-[3-(5-Iodobenzo[b]furan-3-yl)propyl]acetamide

[0417] Starting compound: Preparation 46

[0418] Preparation 80:N-[(2-Benzyl-5-iodobenzo[b]thiophen-3-yl)methyl]acetamide

[0419] Starting compound: Preparation 47

[0420] Preparation 81:N-[2-(5-Iodo-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-ethyl]acetamide

[0421] Starting compound: Preparation 48

[0422] Preparation 82:N-[(6-Iodo-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

[0423] Starting compound: Preparation 39

[0424] Preparation 83:N-[2-(6-Iodo-3,4-dihydro-2H-4-chromenyl)ethyl]-2-phenylacetamide

[0425] Starting compound: Preparation 49

[0426] Preparation 84:N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]acetamide

[0427] Starting compound: Preparation 50

[0428] Preparation 85:N-[2-(6-Iodo-3,4-dihydro-2H-4-thiochromenyl)ethyl]acetamide

[0429] Starting compound: Preparation 51

[0430] Preparation 86:N-[2-(7-Iodo-1,4-benzodioxin-2-yl)ethyl]-N′-propylurea

[0431] Starting compound: Preparation 52

[0432] Preparation 87:N-[2-(6-Iodo-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

[0433] Starting compound: Preparation 53

[0434] Preparation 88:N-[(9-Iodo-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclopropyl-acetamide

[0435] Starting compound: Preparation 54

[0436] Preparation 89:N-(4-Iodo-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

[0437] Starting compound: Preparation 55

[0438] Preparation 90:N-Cyclobutyl-6-iodo-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

[0439] Starting compound: Preparation 56

[0440] Preparation 91:N-[2-(7-Iodo-3-naphthyl-1-naphthyl)ethyl]heptanamide

[0441] Starting compound: Preparation 57

[0442] Preparation 92: N-[2-(7-Iodo-1-naphthyl)ethyl]acetamide

[0443] Starting compound: Preparation 58

[0444] Preparation 93: N-[2-(7-Iodo-1-naphthyl)ethyl]-3-butenamide

[0445] Starting compound: Preparation 59

[0446] Preparation 94: N-[2-(7-Iodo-1-naphthyl)ethyl]-2-bromoacetamide

[0447] Starting compound: Preparation 60

[0448] Preparation 95:N-[2-(7-Iodo-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

[0449] Starting compound: Preparation 61

[0450] Preparation 96: N-Cyclohexyl-4-(7-iodo-1-naphthyl)butanamide

[0451] Starting compound: Preparation 38

[0452] Preparation 97: N-[3-(7-Iodo-1-naphthyl)propyl]acetamide

[0453] Starting compound: Preparation 62

[0454] Preparation 98:N-[2-(2-Iodo-1-naphthyl)-1-methylethyl]propanamide

[0455] Starting compound: Preparation 63

[0456] Preparation 99:N-{2-[7-Iodo-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

[0457] Starting compound: Preparation 64

[0458] Preparation 100: N-Methyl-4-(5-iodobenzo[b]furan-3-yl)butanamide

[0459] Starting compound: Preparation 65

[0460] Preparation 101:N-[2-(5-Iodothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

[0461] Starting compound: Preparation 66

[0462] Preparation 102: N-[2-(5-Iodo-1H-3-indolyl)ethyl]benzamide

[0463] Starting compound: Preparation 67

[0464] Preparation 103:N-[2-(2-Benzyl-5-iodobenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

[0465] Starting compound: Preparation 68

[0466] Preparation 104:N-[(6-Iodo-2-phenyl-2H-3-chromenyl)methyl]butanamide

[0467] Starting compound: Preparation 69

[0468] Preparation 105:N-[2-(6-Iodo-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

[0469] Starting compound: Preparation 70

[0470] Preparation 106: N-[2-(7-Iodo-3-phenyl-1-naphthyl)ethyl]acetamide

[0471] Starting compound: Preparation 71

[0472] Preparation 107:N-[2-(7-Iodo-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

[0473] Starting compound: Preparation 72.1

[0474] Preparation 108: N-[2-(5-Iodobenzo[b]furan-3-yl)ethyl]acetamide

[0475] Starting compound: Preparation 72

[0476] Preparation 109:N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide

[0477] Step A: N-[2-(7-Vinyl-1-naphthyl)ethyl]-2-phenylacetamide

[0478] 15 mmol of the product obtained in Preparation 73, 16 mmol ofvinyltributyltin and 0.43 mmol of tetrakis(triphenylphosphine)palladiumare heated in 30 ml of N-methylpyrrolidinone at 110° C. for 3 hours,with stirring. After evaporating off the solvent, the residue is takenup in 20 ml of dichloromethane and treated with 10% aqueous potassiumfluoride solution. After extraction, concentration under reducedpressure and chromatography on silica gel, the pure title product isobtained.

[0479] Step B: N-[2-(7-Formyl-1-naphthyl)ethyl]-2-phenylacetamide

[0480] To a solution of 10 mmol of the product obtained in Step A in amixture of 50 ml of dioxane and 25 ml of water there are added, atambient temperature, 1.10 g of osmium tetroxide in 2-methyl-2-propanoland then 8.70 g of sodium periodate. After stirring overnight at ambienttemperature, the suspension is filtered and the filtrate is concentratedunder reduced pressure. The residue obtained is taken up indichloromethane. The organic phase is washed with water, dried andevaporated. The residue is purified by chromatography on silica gel toyield the title product.

[0481] Step C: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthoic acid

[0482] 2.7 g of potassium permanganate in 50 ml of an acetone/watermixture (50/50) are added, at ambient temperature, to a solution of 6.88mmol of the product obtained in Step B in 30 ml of acetone. The solutionis stirred for 2 hours at ambient temperature and is then filtered. Thefiltrate is concentrated under reduced pressure and chromatographed onsilica gel to yield the title product.

[0483] Step D: 8-{2-[(2-Phenylacetyl)amino]ethyl}-2-naphthalenecarbonylchloride

[0484] 5 mmol of the product obtained in Step C are dissolved in 40 mlof thionyl chloride. After stirring under an inert atmosphere for 1hour, the thionyl chloride is evaporated off under reduced pressure toyield the title product.

[0485] Step E: N-[2-(7-Amino-1-naphthyl)ethyl]-2-phenylacetamide

[0486] A solution of the product obtained in Step D (20 mmol) indichloromethane (30 ml) containing tetrabutylammonium bromide (20 mg) iscooled in an ice bath. After adding sodium azide (24 mmol) dissolved in5 ml of water, the solution is stirred vigorously at 0° C. for 2 hours.The organic phase is separated off, washed with water (2×5 ml) and driedover magnesium sulphate. After filtration, trifluoroacetic acid (30mmol) is added and the solution is stirred under reflux for 60 hours.After cooling, the organic phase is washed with saturated sodiumhydrogen carbonate solution (2×5 ml) and is concentrated under reducedpressure. The residue is then taken up in methanol (20 ml); water (80ml) and then potassium carbonate (30 mmol) are added. After stirring atambient temperature for 20 hours, the reaction mixture is concentratedunder reduced pressure to a volume of about 60 ml and is then extracted3 times with ether (3×50 ml). After drying over sodium sulphate, theorganic phase is filtered and then evaporated under reduced pressure.The residue is chromatographed on silica gel to yield the title product.

[0487] In Preparations 110 to 134 the procedure is as in Example 109,starting from the appropriate substrate.

[0488] Preparation 110: N-[2-(7-Amino-1-naphthyl)ethyl]-2-bromoacetamide

[0489] Starting compound: Preparation 94

[0490] Preparation 111:N-[2-(7-Amino-8-hexyl-1-naphthyl)ethyl]-2-phenylacetamide

[0491] Starting compound: Preparation 95

[0492] Preparation 112: N-Cyclohexyl-4-(7-amino-1-naphthyl)butanamide

[0493] Starting compound: Preparation 96

[0494] Preparation 113: N-[3-(7-Amino-1-naphthyl)propyl]acetamide

[0495] Starting compound: Preparation 97

[0496] Preparation 114:N-[2-(2-Amino-1-naphthyl)-1-methylethyl]propanamide

[0497] Starting compound: Preparation 98

[0498] Preparation 115:N-[2-(7-Amino-3-benzoyl-1-naphthyl)ethyl]-N′-propylurea

[0499] Starting compound: Preparation 78

[0500] Preparation 116: N-[2-(7-Amino-1-naphthyl)ethyl]-3-butenamide

[0501] Starting compound: Preparation 93

[0502] Preparation 117: N-[2-(7-Amino-1-naphthyl)ethyl]acetamide

[0503] Starting compound: Preparation 92

[0504] Preparation 118:N-{2-17-Amino-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

[0505] Starting compound: Preparation 99

[0506] Preparation 119: N-Methyl-4-(5-aminobenzo[b]furan-3-yl)butanamide

[0507] Starting compound: Preparation 100

[0508] Preparation 120:N-[2-(5-Aminothieno[3,2-b]pyridin-3-yl)ethyl]acetamide

[0509] Starting compound: Preparation 101

[0510] Preparation 121: N-[2-(5-Amino-1H-3-indolyl)ethyl]benzamide

[0511] Starting compound: Preparation 102

[0512] Preparation 122:N-{2-[5-Amino-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]ethyl}acetamide

[0513] Starting compound: Preparation 81

[0514] Preparation 123:N-[2-(5-Amino-2-benzylbenzo[b]furan-3-yl)ethyl]-1-cyclopropane-carboxamide

[0515] Starting compound: Preparation 103

[0516] Preparation 124:N-[(6-Amino-3,4-dihydro-2H-3-chromenyl)methyl]acetamide

[0517] Starting compound: Preparation 82

[0518] Preparation 125:N-[(6-Amino-2-phenyl-2H-3-chromenyl)methyl]butanamide

[0519] Starting compound: Preparation 104

[0520] Preparation 126:N-[2-(6-Amino-2,3-dihydro-1,4-benzodioxin-5-yl)ethyl]acetamide

[0521] Starting compound: Preparation 87

[0522] Preparation 127:N-[(9-Amino-2,3-dihydro-1H-benzo[f]chromen-2-yl)methyl]-2-cyclo-propylacetamide

[0523] Starting compound: Preparation 88

[0524] Preparation 128:N-(4-Amino-2,3-dihydro-1H-2-phenalenyl)-N′-cyclopropylthiourea

[0525] Starting compound: Preparation 89

[0526] Preparation 129:N-[2-(7-Amino-3-phenyl-1-naphthyl)ethyl]acetamide

[0527] Starting compound: Preparation 106

[0528] Preparation 130:N-Cyclobutyl-6-amino-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

[0529] Starting compound: Preparation 90

[0530] Preparation 131:N-[2-(7-Amino-3-naphthyl-1-naphthyl)ethyl]heptanamide

[0531] Starting compound: Preparation 91

[0532] Preparation 132: N-[2-(5-Aminobenzo[b]furan-3-yl)ethyl]acetamide

[0533] Starting compound: Preparation 108

[0534] Preparation 133:N-[2-(7-Amino-1,2,3,4-tetrahydro-1-naphthyl)ethyl]acetamide

[0535] Starting compound: Preparation 107

[0536] Preparation 134:N-[2-(6-Amino-2,3-dihydro-1H-1-indenyl)ethyl]acetamide

[0537] Starting compound: Preparation 105

[0538] Preparations 135 to 145 are obtained by proceeding as inPreparation 1, starting from the appropriate substrate.

[0539] Preparation 135: N-[2-(7-Hydroxy-1-naphthyl)ethyl]-2-furamide

[0540] Preparation 136: N-[2-(7-Hydroxy-1-naphthyl)ethyl]benzamide

[0541] Preparation 137:N-[2-(7-Hydroxy-1-naphthyl)ethyl]cyclopropanecarboxamide

[0542] Preparation 138:N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]benzamide

[0543] Preparation 139:N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]-2-furamide

[0544] Preparation 140:N-[2-(5-Hydroxy-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

[0545] Preparation 141:N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]cyclopropanecarboxamide

[0546] Preparation 142:N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

[0547] Preparation 143:N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0548] Preparation 144:N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

[0549] Preparation 145:N-[2-(5-Hydroxy-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

[0550] Preparation 146:N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

[0551] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 142.

[0552] Preparation 147:N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

[0553] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 146.

[0554] Preparation 148:N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]acetamide

[0555] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 147.

[0556] Preparation 149:N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

[0557] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 145.

[0558] Preparation 150:N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

[0559] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 149.

[0560] Preparation 151:N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]-2-furamide

[0561] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 150.

[0562] Preparation 152:N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

[0563] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 144.

[0564] Preparation 153:N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

[0565] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 152.

[0566] Preparation 154:N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]benzamide

[0567] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 153.

[0568] Preparation 155:N-[2-(5-Bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0569] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 143.

[0570] Preparation 156:N-[2-(5-Iodo-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0571] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 155.

[0572] Preparation 157:N-[2-(5-Amino-1H-pyrrolo[2,3-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0573] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 156.

[0574] Preparation 158:N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0575] The procedure is as in Preparation 1.

[0576] Preparation 159:N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0577] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 158.

[0578] Preparation 160:N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0579] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 159.

[0580] Preparation 161:N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]cyclopropane-carboxamide

[0581] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 160.

[0582] Preparation 162:N-[2-(5-Hydroxy-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

[0583] The procedure is as in Preparation 1.

[0584] Preparation 163:N-[2-(5-Bromo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

[0585] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 162.

[0586] Preparation 164:N-[2-(5-Iodo-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

[0587] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 163.

[0588] Preparation 165:N-[2-(5-Amino-1H-pyrrolo[3,2-b]pyridin-3-yl)ethyl]acetamide

[0589] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 164.

[0590] Preparation 166:N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

[0591] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 140.

[0592] Preparation 167:N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

[0593] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 166.

[0594] Preparation 168:N-[2-(5-Amino-1-benzofuran-3-yl)ethyl]cyclopropanecarboxamide

[0595] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 167.

[0596] Preparation 169:N-[2-(5-Hydroxy-1-benzothiophen-3-yl)ethyl]benzamide

[0597] The procedure is as in Preparation 1.

[0598] Preparation 170:N-[2-(5-Bromo-1-benzothiophen-3-yl)ethyl]benzamide

[0599] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 169.

[0600] Preparation 171:N-[2-(5-Iodo-1-benzothiophen-3-yl)ethyl]benzamide

[0601] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 170.

[0602] Preparation 172:N-[2-(5-Amino-1-benzothiophen-3-yl)ethyl]benzamide

[0603] The procedure is as in Preparation 109, starting from thecompound obtained in Preparation 171.

[0604] Preparation 173: N-[2-(7-Bromo-1-naphthyl)ethyl]-2-furamide

[0605] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 135.

[0606] Preparation 174: N-[2-(7-Iodo-1-naphthyl)ethyl]-2-furamide

[0607] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 173.

[0608] Preparation 175: N-[2-(5-Bromo-1-benzofuran-3-yl)ethyl]benzamide

[0609] The procedure is as in Preparation 40, starting from the compoundobtained in Preparation 138.

[0610] Preparation 176: N-[2-(5-Iodo-1-benzofuran-3-yl)ethyl]benzamide

[0611] The procedure is as in Preparation 73, starting from the compoundobtained in Preparation 176.

EXAMPLE 1

[0612] N-{8-[2-([2-Phenylacetyl]amino)ethyl]-2-naphthyl}butanamide

[0613] A solution of butanoic acid chloride (11 mmol) dissolved in ether(5 ml) is added dropwise to a solution of the product obtained inPreparation 109 (10 mmol) in ether (10 ml) and triethylamine (2 ml). Thesolution is stirred at ambient temperature until the amine hasdisappeared (monitored by TLC). At the end of the reaction, the organicphase is washed with water, dried, concentrated under reduced pressureand chromatographed on silica gel to yield the title product.

EXAMPLE 2

[0614]N-{2-[7-{[(Cyclohexylamino)carbonyl]amino}-1-naphthyl]ethyl}-2-phenylacetamide

[0615] A solution of cyclohexyl isocyanate in dichloromethane (5 ml) isadded to a solution of the product obtained in Preparation 109 (10 mmol)in dichloromethane (10 ml). Stirring is carried out at ambienttemperature until the starting amine has disappeared (monitored by TLC);the reaction mixture is then evaporated and concentrated under reducedpressure and is chromatographed on silica gel to yield the titleproduct.

EXAMPLE 3

[0616]N-{2-[7-([Anilinocarbothioyl]amino)-1-naphthyl]ethyl}-2-phenyl-acetamide

[0617] The procedure is as in Example 2, but the cyclohexyl isocyanateis replaced by phenyl isothiocyanate to obtain the title product.

[0618] In Examples 4 to 16 the procedure is as in Example 1, startingfrom appropriate reactants.

EXAMPLE 4

[0619]N-(8-{2-[(2-Bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexane-carboxamide

[0620] Starting compound: Preparation 110

EXAMPLE 5

[0621]N-{1-Hexyl-8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}benzamide

[0622] Starting compound: Preparation 111

EXAMPLE 6

[0623]N-{6-Benzoyl-8-[2-{[(propylamino)carbonyl]amino}ethyl]-2-naphthyl}-2,2-dimethylpropanamide

[0624] Starting compound: Preparation 115

EXAMPLE 7

[0625] N-{3-[4-(Methylamino)-4-oxobutyl]benzo[b]furan-5-yl}-3-butynamide

[0626] Starting compound: Preparation 119

EXAMPLE 8

[0627]N-{3-[2-(Acetylamino)ethyl]-2-[4-fluorobenzyl]-1-methyl-1H-pyrrolo-[2,3-b]pyridin-5-yl}-3-phenyl-2-propenamide

[0628] Starting compound: Preparation 122

EXAMPLE 9

[0629]N-{3-[(Acetylamino)methyl]-3,4-dihydro-2H-6-chromenyl}-2-phenyl-propanamide

[0630] Starting compound: Preparation 124

EXAMPLE 10

[0631]N-{5-[2-(Acetylamino)ethyl]-2,3-dihydro-1,4-benzodioxin-6-yl}-hexanamide

[0632] Starting compound: Preparation 126

EXAMPLE 11

[0633]N-{2-[([2-Cyclopropylacetyl]amino)methyl]-2,3-dihydro-1H-benzo[f]-chromen-9-yl}-4-(trifluoromethyl)benzamide

[0634] Starting compound: Preparation 127

EXAMPLE 12

[0635]N-{2-[([Cyclopropylamino]carbothioyl)amino]-2,3-dihydro-1H-4-phenalenyl}-4-ethoxybenzamide

[0636] Starting compound: Preparation 128

EXAMPLE 13

[0637]N-{8-[2-(Acetylamino)ethyl]-6-phenyl-2-naphthyl}-1-cyclopentane-carboxamide

[0638] Starting compound: Preparation 129

EXAMPLE 14

[0639]N-Cyclobutyl-6-([2-cyclopropylacetyl)amino]-4,5-dihydro-3H-benzo[cd]-isobenzofuran-4-carboxamide

[0640] Starting compound: Preparation 130

EXAMPLE 15

[0641] N-{8-[2-(Heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide

[0642] Starting compound: Preparation 131

EXAMPLE 16

[0643] N-{2-[6-(Acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide

[0644] Starting compound: Preparation 134

[0645] Examples 17 to 23 are obtained by proceeding as in Example 2,starting from appropriate reactants.

EXAMPLE 17

[0646] N-Cyclohexyl-4-{7-[(anilinocarbonyl)amino]-1-naphthyl}butanamide

[0647] Starting compound: Preparation 112

EXAMPLE 18

[0648]N-{1-Methyl-2-[2-{[([morpholinomethyl]amino)carbonyl]amino}-1-naphthyl]ethyl}propanamide

[0649] Starting compound: Preparation 114

EXAMPLE 19

[0650]N-{2-[7-{[(Benzylamino)carbonyl]amino}-3-(cyclopropylmethyl)-1-naphthyl]ethyl}acetamide

[0651] Starting compound: Preparation 118

EXAMPLE 20

[0652]N-{2-[5-{[(Allylamino)carbonyl]amino}thieno[3,2-b]pyridin-3-yl]ethyl}-acetamide

[0653] Starting compound: Preparation 120

EXAMPLE 21

[0654]N-{2-[2-Benzyl-5-{[(1-ethynylamino)carbonyl]amino}benzo[b]furan-3-yl]ethyl}-1-cyclopropanecarboxamide

[0655] Starting compound: Preparation 123

EXAMPLE 22

[0656]N-{[6-{[([3-Methyl-2-butenyl]amino)carbonyl]amino}-2-phenyl-2H-3-chromenyl]methyl}butanamide

[0657] Starting compound: Preparation 125

EXAMPLE 23

[0658]N-[2-(7-{[(Cyclohexylamino)carbonyl]amino}-3-phenyl-1-naphthyl)-ethyl]acetamide

[0659] Starting compound: Preparation 129

[0660] In Examples 24 to 29 the procedure is as in Example 3, startingfrom appropriate substrates.

EXAMPLE 24

[0661]N-{2-[7-{[(Isobutylamino)carbothioyl]amino}-1-naphthyl]ethyl}-2-bromoacetamide

[0662] Starting compound: Preparation 110

EXAMPLE 25

[0663]N-{3-[7-{[([4-Methylbenzyl]amino)carbothioyl]amino}-1-naphthyl]-propyl}acetamide

[0664] Starting compound: Preparation 113

EXAMPLE 26

[0665]N-Methyl-4-{5-[([1-ethynylamino]carbothioyl)amino]benzo[b]furan-3-yl}butanamide

[0666] Starting compound: Preparation 119

EXAMPLE 27

[0667]N-{2-[5-{[(Butylamino)carbothioyl]amino}-1H-3-indoly]ethyl}-benzamide

[0668] Starting compound: Preparation 121

EXAMPLE 28

[0669]N-{[9-([Anilinocarbothioyl]amino)-2,3-dihydro-1H-benzo[f]chromen-2-yl]methyl}-2-cyclopropylacetamide

[0670] Starting compound: Preparation 127

EXAMPLE 29

[0671]N-Cyclobutyl-6-{[([2,3-dimethyl-2-butenyl]amino)carbothioyl]amino}-4,5-dihydro-3H-benzo[cd]isobenzofuran-4-carboxamide

[0672] Starting compound: Preparation 130

EXAMPLE 30

[0673] N-Ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide

[0674] The procedure is as in Preparation 109, but instead of convertingthe acid chloride into an amine, it is treated with an amine to yieldthe title amide according to the procedure described below.

[0675] A solution of the product obtained in Step D of Preparation 109(3.5 mmol) in ether (10 ml) is added, dropwise, to a solution ofethylamine (4 mmol) in ether (10 ml) and triethylamine (2 ml),maintained between 0 and 5° C. using an ice bath. Stirring is carriedout at ambient temperature until the acid chloride has disappeared andthe reaction mixture is then poured into a mixture of ice (10 g) andconcentrated HCl (0.1 ml). The organic phase is washed with water, driedover magnesium sulphate, concentrated under reduced pressure andchromatographed on silica gel to yield the title product.

[0676] In Examples 31 to 50 the procedure is as in Example 30, but theethylamine and the product of Step D of Preparation 109 are replaced byappropriate substrates.

EXAMPLE 31

[0677]N,N-Diethyl-8-{2-[2-1(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide

[0678] Starting compound: Preparation 74

EXAMPLE 32

[0679]N-Phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide

[0680] Starting compound: Preparation 75

EXAMPLE 33

[0681]N-(1-Ethynyl)-8-{2-[(cyclohexylcarbonyl)amino]ethyl}-2-naphthamide

[0682] Starting compound: Preparation 76

EXAMPLE 34

[0683] N-Benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide

[0684] Starting compound: Preparation 77

EXAMPLE 35

[0685]N-{2-[3-Benzoyl-7-(morpholinocarbonyl)-1-naphthyl]ethyl}-N′-propylurea

[0686] Starting compound: Preparation 78

EXAMPLE 36

[0687] N,N-Diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide

[0688] Starting compound: Preparation 79

EXAMPLE 37

[0689]N-Isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]-thiophene-5-carboxamide

[0690] Starting compound: Preparation 80

EXAMPLE 38

[0691]N,N-Diethyl-3-[2-(acetylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0692] Starting compound: Preparation 81

EXAMPLE 39

[0693] Ethyl2-{[(4-{2-[(2-phenylacetyl)amino]ethyl}-3,4-dihydro-2H-6-chromenyl)carbonyl]amino}acetate

[0694] Starting compound: Preparation 83

EXAMPLE 40

[0695]N-Cyclohexyl-N-(1-ethynyl)-4-[2-(acetylamino)ethyl]-6-thiochroman-carboxamide

[0696] Starting compound: Preparation 85

EXAMPLE 41

[0697]N-Benzyl-3-(2-{[(propylamino)carbonyl]amino}ethyl-1,4-benzodioxin-6-carboxamide

[0698] Starting compound: Preparation 86

EXAMPLE 42

[0699]N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylacetyl)amino]methyl}-2,3,6,10b-tetrahydro-1H-benzo[f]chromene-8-carboxamide

[0700] Starting compound: Preparation 88

EXAMPLE 43

[0701]N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihydro-1H-4-phenalenecarboxamide

[0702] Starting compound: Preparation 89

EXAMPLE 44

[0703]N-Cyclobutyl-N-trityl-4,5-dihydro-3H-benzo[cd]isobenzofuran-4,6-dicarboxamide

[0704] Starting compound: Preparation 90

EXAMPLE 45

[0705] Ethyl2-[({8-[2-heptanoylamino)ethyl]-6-naphthyl-2-naphthyl}carbonyl)-amino]acetate

[0706] Starting compound: Preparation 91

EXAMPLE 46

[0707] N-(1-Ethynyl)-8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthamide

[0708] Starting compound: Preparation 94

EXAMPLE 47

[0709] N-Phenyl-1-hexyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide

[0710] Starting compound: Preparation 95

EXAMPLE 48

[0711] Ethyl2-({[8-[2-(acetylamino)ethyl]-6-(cyclopropylmethyl)-2-naphthyl]-carbonyl}amino)acetate

[0712] Starting compound: Preparation 99

EXAMPLE 49

[0713]N-(1-Ethynyl)-2-benzyl-3-{2-[(cyclopropylcarbonyl)amino]ethyl}benzo-[b]furan-5-carboxamide

[0714] Starting compound: Preparation 103

EXAMPLE 50

[0715]N-(1-Isopropyl-2-propynyl)-3-[(butynylamino)methyl]-2-phenyl-2H-6-chromenecarboxamide

[0716] Starting compound: Preparation 104

EXAMPLE 51

[0717]N-Phenyl-8-(2-{methyl[(propylamino)carbothioyl]amino}ethyl)-2-naphthalenecarbothioamide

[0718] The product obtained in Example 32 is treated with Lawesson'sreagent to yield the title compound.

[0719] In Examples 52 to 57 the procedure is as in Example 51, takingthe appropriate starting substrate.

EXAMPLE 52

[0720]N-Benzyl-1-{2-[(2,2,2-trifluoroethanethioyl)amino]ethyl}-2-naphthalene-carbothioamide

[0721] Starting compound: Example 34

EXAMPLE 53

[0722]N,N-Diphenyl-3-[3-(ethanethioylamino)propyl]benzo[b]furan-5-carbothioamide

[0723] Starting compound: Example 36

EXAMPLE 54N,N-Diethyl-3-[2-(ethanethioylamino)ethyl]-2-(4-fluorobenzyl)-1-methyl-1H-pyrrolo[2,3-b]pyridine-5-carbothioamide

[0724] Starting compound: Example 38

EXAMPLE 55

[0725]N-Cyclohexyl-N-(1-ethynyl)-4-[2-(ethanethioylamino)ethyl]-6-thiochromancarbothioamide

[0726] Starting compound: Example 40

EXAMPLE 56

[0727]N-(3-Methyl-2-butenyl)-2-{[(2-cyclopropylethanethioyl)amino]methyl}-2,3,6,10b-tetrahydro-1H-benzo[f]chromene-8-carbothioamide

[0728] Starting compound: Example 42

EXAMPLE 57

[0729]N-[3-Phenyl-2-propenyl]-2-{[(cyclopropylamino)carbothioyl]amino}-2,3-dihydro-1H-4-phenalenecarbothioamide

[0730] Starting compound. Example 43

[0731] In Examples 58 to 61 the procedure is as in Example 1, but theacid chloride is replaced by the corresponding halogenocarboxylate.

EXAMPLE 58

[0732] Methyl N-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate

[0733] Starting compound: Preparation 132

[0734] Melting point=138-140° C.

EXAMPLE 59

[0735] Ethyl N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate

[0736] Starting compound: Preparation 110

EXAMPLE 60

[0737] Methyl N-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate

[0738] Starting compound: Preparation 129

EXAMPLE 61

[0739] HexylN-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}-carbamate

[0740] Starting compound: Preparation 133

EXAMPLE 62

[0741] N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide

[0742] Step A: 3-Acetyl-4-hydroxybenzoic acid

[0743] 166 mmol of aluminium chloride are added slowly to 150 ml ofnitrobenzene. 83 mmol of 4-acetylbenzoic acid are then added and heatingis carried out at 120° C. for 2 hours. The mixture is hydrolysed using1.2 litres of ice-cold water and the aqueous phase is acidified with 20ml of concentrated HCl. Then, extraction with ethyl acetate and washingwith aqueous 5% sodium carbonate solution are carried out. The aqueousphase is acidified with 6N HCl and the precipitate obtained is dried andrecrystallised.

[0744] Melting point=120-121° C.

[0745] Step B: 3-(2-Bromoacetyl)-4-hydroxybenzoic acid

[0746] The compound obtained in Step A (32.2 mmol) is dissolved inglacial acetic acid (40 ml) and then 48.3 mmol of bromine are added. Themixture is heated at 80° C. for 2 hours and is then hydrolysed usingice-cold water. The precipitate obtained is filtered off, washed withwater until a pH of 5-6 is obtained, and then dried and recrystallised.

[0747] Melting point=174-1 75° C.

[0748] Step C: Methyl 3-bromoacetyl-4-hydroxybenzoate

[0749] The compound obtained in Step B (27.4 mmol) is dissolved in 150ml of MeOH, and 54.8 mmol of thionyl chloride are added dropwise in thecold state. The mixture is then stirred for 1 hour at ambienttemperature and then for 2 hours at reflux. After evaporating off themethanol and the thionyl chloride, the oily residue is taken up inAcOEt, washed with water and then dried over MgSO₄. The solvent isevaporated off under reduced pressure and the solid obtained isrecrystallised.

[0750] Melting point=93-94° C.

[0751] Step D: 5-(Methoxycarbonyl-3-benzo[b]furan-3-yl)acetonitrile

[0752] The compound obtained in Step C (15 mmol) is dissolved in 35 mlof acetone. 30 mmol of potassium carbonate are added and the mixture isstirred for 2 hours at ambient temperature. The precipitate formed isfiltered off, washed with acetone and the filtrate is evaporated underreduced pressure. The benzofiranone formed is used directly in thefollowing step:

[0753] 22.5 mmol of NaH are introduced into a 250 ml round-bottomedtwo-necked flask which is placed in a bath of ice/salt and under anitrogen atmosphere. 22.5 mmol of diethyl cyanophosphonate are addeddropwise and the mixture is then stirred for 20 minutes. Thebenzofuranone previously obtained, in 140 ml of anhydrous THF, is addedand the mixture is stirred for 2 hours at ambient temperature. Afterhydrolysing on a pile of ice and extracting with Et₂O, the organic phaseis dried over MgSO₄ and the solvent is then evaporated off under reducedpressure. The title compound is purified by chromatography on a silicagel column (eluant: CH₂Cl₂), and is then recrystallised.

[0754] Melting point=125-126° C.

[0755] Step E: N-[2-(5-Methoxycarbonylbenzo[b]furan-3-yl)ethyl]acetamide

[0756] The 5-(methoxycarbonylbenzo[b]furan-3-yl)acetonitrile obtained inStep D (6.46 mmol) is dissolved in acetic anhydride (30 ml) in anautoclave, and 14.4 mmol of Raney nickel are added. After stirringovernight at 60° C. and under a hydrogen pressure of 60 bars, thecatalyst is filtered off and washed with methanol. The filtrate isevaporated to dryness and the chestnut-coloured precipitate obtained ischromatographed on a silica gel column using ethyl acetate as eluant andis then recrystallised.

[0757] Melting point=121-122° C.

[0758] Elemental Microanalysis: C H N % calculated: 64.36 5.78 5.36 %found: 64.14 5.81 5.28

EXAMPLE 63

[0759] Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate

[0760] Step A: Methyl 3-(2-aminoethyl)-1-benzofuran-5-carboxylatehydrochloride

[0761] 6.57 mmol of the compound obtained in Step D of Example 62 aredissolved in 150 ml of methanol. The solution is introduced into anautoclave and 28.8 mmol of Raney nickel are added. The solution issaturated with ammonia, and then hydrogen is introduced until a pressureof 60 bars is obtained. The solution is stirred for 4 hours at atemperature of 60° C. After cooling, the catalyst is filtered off, andthe methanol is then evaporated off. The residue is purified bychromatography on a silica gel column using a mixture ofdichloromethane/methanol (7/3) and then methanol as eluant. The amineobtained is dissolved in absolute ethanol. Stirring is carried out in anice bath and gaseous hydrogen chloride is bubbled through. Thehydrochloride obtained is filtered off under suction and dried in adesiccator.

[0762] Melting point=210-211° C.

[0763] Step B: Methyl3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate

[0764] 1 mmol of the compound obtained in Step A is introduced into 30ml of anhydrous CH₂Cl₂. The temperature is lowered with the aid of anice bath, and 1.5 mmol of triethylamine and then 1.5 mmol of 2-furoicacid chloride are added dropwise in succession. The mixture is stirredfor 20 minutes, and the organic phase is then washed with water, driedover MgSO₄ and evaporated. The residue is purified by chromatography ona silica gel column and the title product is recrystallised.

[0765] Melting point=116-118° C.

[0766] Elemental Microanalysis: C H N % calculated: 65.17 4.82 4.47 %found: 64.80 4.84 4.50

EXAMPLE 64

[0767] Methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}1-benzofuran-5-carboxylate

[0768] The procedure is as in Example 63.

[0769] Melting point=122-123° C.

EXAMPLE 65

[0770] Methyl3-[2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate

[0771] The procedure is as in Example 63.

[0772] Melting point=154-155° C.

EXAMPLE 66

[0773] Methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate

[0774] Vinylacetic acid (1 mmol),1-ethyl-3-(3-dimethylaminopropyl-3-ethyl)carbodiimide hydro-chloride(E.D.C.) (1.1 mmol) and hydroxybenzotriazole (HOBT) (1.1 mmol) aredissolved in dichloromethane (30 ml) in a flask cooled to −20° C. After30 minutes, the compound obtained in Step A of Example 63 (1 mmol),dissolved in dichloromethane (20 ml), is added dropwise. The reactionmixture is stirred for 30 minutes at −20° C. and then overnight atambient temperature. The dichloromethane is evaporated off and theresidue is purified by chromatography on a silica gel column.

[0775] Melting point=98-100° C.

EXAMPLE 67

[0776] 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxamide

[0777] The ester (0.1 mol) obtained in Example 62, dissolved in anaqueous 20% ammonium hydroxide solution (50 ml), is heated for 5 hoursat 60° C. The reaction mixture is cooled and is then evaporated todryness. The residue obtained is purified by chromatography on a silicagel column.

[0778] Melting point=206-208° C.

[0779] Elemental Microanalysis: C H N % calculated: 63.40 5.73 11.38 %found: 63.23 5.89 11.17

EXAMPLE 68

[0780]3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide

[0781] The same procedure is used as in Example 67.

[0782] Melting point=209-210° C.

EXAMPLE 69

[0783] 3-[2-(2-Furoylamino)ethyl]-1-benzofuran-5-carboxamide

[0784] The same procedure is used as in Example 67.

[0785] Melting point=110-112° C.

[0786] Elemental Microanalysis: C H N % calculated: 64.42 4.73 9.39 %found: 64.23 4.98 9.97

EXAMPLE 70

[0787]3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide

[0788] To the ester obtained in Example 62 (1 mmol), dissolved inmethanol (40 ml) in the hot state, there is added an aqueous 40%methylamine solution (1.6 mmol), and the mixture is refluxed for 2hours. The reaction mixture is then cooled and the methanol issubsequently evaporated off. The aqueous phase is extracted with ethylacetate, the organic phase is dried over magnesium sulphate and thesolvent is evaporated off. The residue is purified by chromatography ona silica gel column.

[0789] Melting point=188-189° C.

[0790] Elemental Microanalysis: C H N % calculated: 67.11 6.34 9.78 %found: 67.00 6.34 9.77

EXAMPLE 71

[0791] 3-[2-(Acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide

[0792] The same procedure is used as in Example 70.

[0793] Melting point=158-159° C.

[0794] Elemental Microanalysis: C H N % calculated: 64.59 6.20 10.76 %found: 64.27 6.13 10.44

EXAMPLE 72

[0795]3-{2-[(Cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide

[0796] The same procedure is used as in Example 70.

[0797] Melting point=170-171 ° C.

EXAMPLE 73

[0798] 3-[2-(Benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide

[0799] The same procedure is used as in Example 70.

EXAMPLE 74

[0800]N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide

[0801] Step A: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carboxylic acid

[0802] To the ester obtained in Example 62 (2 mmol), dissolved inmethanol (90 ml), there is added aqueous 30% sodium hydroxide solution(30 ml), and the mixture is stirred overnight. After evaporating off themethanol, the temperature of the reaction mixture is lowered with theaid of an ice bath and the mixture is acidified with hydrochloric acidsolution (6N). The aqueous phase is extracted with ethyl acetate, andthe organic phase is dried over magnesium sulphate and then evaporatedto dryness. The residue obtained is recrystallised.

[0803] Melting point=210-211° C.

[0804] Step B: 3-[2-(Acetylamino)ethyl]-1-benzofuran-5-carbonyl azide

[0805] The acid (1 mmol) obtained in Step A is dissolved in acetone. Thetemperature of the reaction mixture is lowered with the aid of an icebath, and triethylamine (1.5 mmol) and then ethyl chloroformate (1.5mmol) are added. After stirring for 15 minutes, sodium azide (1.5 mmol),previously dissolved in water (1 ml of water per 400 mg of sodiumazide), is added and stirring is again carried out for 10 minutes. Themixture is extracted with ethyl acetate, and the organic phase is thenwashed with water, dried over magnesium sulphate and evaporated todryness. The azide obtained is used, without additional purification, inthe following Step.

[0806] Step C:N-{3-[2-(Acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide

[0807] To the azide obtained in Step B (460 mg, 1.68 mmol), dissolved indichloromethane, there is added trifluoroacetic acid (1.82 ml, 2.35mmol) and stirring is carried out overnight. The reaction mixture iswashed with water and then with aqueous 10% sodium hydrogen carbonatesolution.

[0808] The organic phase is dried over magnesium sulphate and thenevaporated. The residue obtained is purified by chromatography on asilica gel column using ethyl acetate as eluant.

[0809] Melting point=152-154° C.

EXAMPLE 75

[0810] Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate

[0811] The azide obtained in Step B of Example 74 (1 mmol) is heated at80° C. overnight and 5 ml of MeOH and 5 ml of toluene are added. Afterevaporating off the solvent, the residue obtained is purified bychromatography on a silica gel column.

[0812] Melting point=153-155° C.

[0813] Elemental Microanalysis: C H N % calculated: 63.56 6.00 9.27 %found: 63.27 6.02 9.14

EXAMPLE 76

[0814] tert-Butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate

[0815] The procedure is as in Examples 74 and 75.

[0816] Melting point=146-148° C.

[0817] Elemental Microanalysis: C H N % calculated: 64.12 6.97 8.79 %found: 64.03 6.58 8.67

EXAMPLE 77

[0818] tert-Butyl3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate

[0819] To 1.98 mmol of the carbamate obtained in Example 76, dissolvedin dimethylformamide, there are added, in the cold state, 2.18 mmol ofsodium hydride, and stirring is carried out for 2 hours at ambienttemperature. 2.37 mmol of methyl iodide are added to the mixture andstirring is carried out for 4 hours at ambient temperature. The reactionmixture is hydrolysed, extracted with ethyl acetate, and the organicphase is then washed with water and dried over magnesium sulphate. Theresidue is recrystallised.

EXAMPLE 78

[0820] Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate

[0821] The procedure is as in Examples 74 and 75.

EXAMPLE 79

[0822] Methyl 3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate

[0823] The procedure is as in Examples 74 and 75.

EXAMPLE 80

[0824] N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide

[0825] Step A: N-{2-[7-(Benzylthio)-1-naphthyl]ethyl}acetamide

[0826] 4.4 mmol of the compound obtained in Preparation 1 are dissolvedin 20 ml of anhydrous CH₂Cl₂ and placed under a current of nitrogen. 6.5mmol of benzylthiol are added dropwise using a syringe and then 8.8 mmolof triflic acid are added, before the mixture is refluxed for 24 hours.After cooling, hydrolysis is carried out using 10% Na₂CO₃ solution. Theorganic phase is washed with 10% sodium hydroxide solution and then withwater until the washing waters are neutral, and is then dried andevaporated. The residue is taken up in petroleum ether andrecrystallised from a toluene/cyclohexane mixture.

[0827] Melting point=80-83° C.

[0828] Step B: 8-[2-(Acetylamino)ethyl]-2-naphthalenesulphonyl chloride

[0829] 3 mmol of the compound obtained in Step A are crushed in amortar, together with 13.1 mmol of iodosobenzene and 107 g ofsilica/HCl, with the aid of a pestle. Dichloromethane is added and thesilica is filtered off and washed several times with CH₂Cl₂. Thefiltrate obtained is evaporated and the residue is taken up in petroleumether and then filtered.

[0830] Step C: N-{2-[7-(Aminosulphonyl)-1-naphthyl]ethyl}acetamide

[0831] 0.8 mmol of the compound obtained in Step B is dissolved in 10 mlof CH₂Cl₂ and then 1.2 mmol of triethylamine are added. The mixture iscooled with the aid of an ice bath and 1.2 mmol of ammonium hydroxidesolution are added dropwise. After stirring for 2 hours, the mixture isevaporated and the residue obtained is recrystallised.

[0832] Melting point=194-196° C.

EXAMPLE 81

[0833] N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide

[0834] The procedure is as in Example 80, but the ammonium hydroxide inStep C is replaced by methylamine.

[0835] Melting point=155-156° C.

[0836] By proceeding as in Example 80, but replacing, in Step A, thecompound of Preparation 1 by the appropriate substrate, and, in Step C,the ammonium hydroxide by the appropriate amine, Examples 82 to 84 areobtained:

EXAMPLE 82

[0837] N-(2-{7-[(Methylamino)sulphonyl]-1-naphthy}ethyl)-2-furamide

[0838] Starting compound: Preparation 135

EXAMPLE 83

[0839] N-(2-{7-[(Ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide

[0840] Starting compound: Preparation 136

EXAMPLE 84

[0841]N-(2-{7-[(Methylamino)sulphonyl]-1-naphthyl}ethyl)cyclopropane-carboxamide

[0842] Starting compound: Preparation 137

EXAMPLE 85

[0843]N-(3-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide

[0844] Starting compound: Preparation 16

EXAMPLE 86

[0845]N-(2-{5-[(Propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide

[0846] Starting compound: Preparation 18

EXAMPLE 87

[0847]N-(2-{5-[(Cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-benzamide

[0848] Starting compound: Preparation 138

EXAMPLE 88

[0849]N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide

[0850] Starting compound: Preparation 139

EXAMPLE 89

[0851]N-(2-{5-[(Hexylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carboxamide

[0852] Starting compound: Preparation 140

EXAMPLE 90

[0853]N-(2-{5-[(Methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropane-carboxamide

[0854] Starting compound: Preparation 140

EXAMPLE 91

[0855]N-(2-{2-Benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-acetamide

[0856] Starting compound: Preparation 19

EXAMPLE 92

[0857]N-(2-{5-1(Isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)-cyclopropanecarboxamide

[0858] Starting compound: Preparation 141

EXAMPLE 93

[0859]N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-acetamide

[0860] Starting compound: Preparation 142

EXAMPLE 94

[0861]N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-cyclopropanecarboxamide

[0862] Starting compound: Preparation 143

EXAMPLE 95

[0863]N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-benzamide

[0864] Starting compound: Preparation 144

EXAMPLE 96

[0865]N-(2-{5-[(Methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamide

[0866] Starting compound: Preparation 145

[0867] Examples 97 to 105 are obtained by proceeding as in Example 1,but replacing the acid chloride by the correspondinghalogenocarboxylate.

EXAMPLE 97

[0868] Methyl5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate

[0869] Starting compound: Preparation 126

EXAMPLE 98

[0870] Methyl3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate

[0871] Starting compound: Preparation 124

EXAMPLE 99

[0872] Ethyl3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate

[0873] Starting compound: Preparation 134

EXAMPLE 100

[0874] Methyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

[0875] Starting compound: Preparation 148

EXAMPLE 101

[0876] Methyl3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

[0877] Starting compound: Preparation 151

EXAMPLE 102

[0878] Methyl3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate

[0879] Starting compound: Preparation 154

EXAMPLE 103

[0880] Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]-pyridin-5-yl-carbamate

[0881] Starting compound: Preparation 157

[0882] EXAMPLE 104

[0883] Methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[3,2-b]-pyridin-5-yl-carbamate

[0884] Starting compound: Preparation 161

EXAMPLE 105

[0885] Ethyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[3,2-b]pyridin-5-yl-carbamate

[0886] Starting compound: Preparation 165

[0887] Examples 106 to 108 are obtained by proceeding as in Example 1,starting from the appropriate substrate.

EXAMPLE 106

[0888] N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}acetamide

[0889] Starting compound: Preparation 117

EXAMPLE 107

[0890]N-{2-[5-(Acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropane-carboxamide

[0891] Starting compound: Preparation 168

EXAMPLE 108

[0892] N-{2-[5-(Acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide

[0893] Starting compound: Preparation 172

[0894] Examples 109 to 112 are obtained by proceeding as in Preparation109, condensing the appropriate amine with the intermediate acidchloride.

EXAMPLE 109

[0895]3-[2-(Acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide

[0896] Starting compound: Preparation 147

EXAMPLE 110

[0897] N-(2-{7-[(Methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide

[0898] Starting compound: Preparation 174

EXAMPLE 111

[0899]3-{2-[(Cyclopropylcarbonyl)amino]ethyl}-N-ethyl-1-benzofuran-5-carboxamide

[0900] Starting compound: Preparation 167

EXAMPLE 112

[0901] 3-[2-(Benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide

[0902] Starting compound: Preparation 176

EXAMPLE 113

[0903]N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide

[0904] Step A: 7-Nitro-3,4-dihydro-1(2H)-naphthalenone

[0905] 7 mmol of 1-oxo-1,2,3,4-tetrahydronaphthalene and 5 ml ofconcentrated sulphuric acid are cooled in a freezer for 30 minutes. Thereaction mixture is then placed in a bath of alcohol at −15° C. on acooling plate. A sulphonitric mixture (1.1 ml of sulphuric acid and 0.73ml of nitric acid) is prepared and brought to the temperature of thereaction mixture before being added dropwise, avoiding any drasticheating of the mixture. Stirring is carried out for 15 minutes and thenhydrolysis on a pile of ice is carried out. The pale yellow precipitateobtained is washed with water until the washing waters have a neutral pHand is then dried in a desiccator and purified on a silica gel column.

[0906] Melting point=103.7-104.3° C.

[0907] Step B:2-[7-Nitro-3,4-dihydro-1(2H)-naphthalenylidene]acetonitrile

[0908] Using a 50 ml two-necked flask under a current of nitrogen andplaced in a bath of alcohol at −15° C., 0.32 g of sodium hydride isadded in portions to 40 ml of THF, with magnetic stirring, and then 1.4g of diethyl cyanomethylphosphonate in 10 ml of THF are added dropwise.After stirring for half an hour, when the mixture is highly homogeneous,the flask is plunged into a medium at −78° C. (cryostat), and 1 g of thecompound obtained in Step A, dissolved in 20 ml of THF, is addeddropwise. Stirring under a current of nitrogen is carried out for 2hours. The reaction mixture is then brought to ambient temperature,hydrolysed on ice and precipitated. After filtering under suction andwashing with water until the washing waters have a neutral pH,extraction with 3 volumes of ether is carried out. The organic phasesare washed with 3 volumes of water and then dried. The grey solidobtained is decolorised on carbon.

[0909] Melting point=98.1-98.5° C.

[0910] Step C:N-{8-[2-(Acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}acetamide

[0911] 9 mmol of the compound obtained in Step B are dissolved in aceticanhydride (100 ml) and then a small spatula of sodium acetate is added.The mixture is introduced into an autoclave, Raney nickel is added andautoclaving under a pressure of 40 bars is carried out for 6 hours, withstirring at 50-60° C. The mixture is filtered and is rinsed with alcoholat 95° C.; the solvent is then evaporated off. Hydrolysis is carried outusing 100 ml of distilled water and extraction with 3 volumes ofdichloromethane is carried out. The organic phase is washed with 2volumes of water, dried over magnesium sulphate, filtered andevaporated. Rinsing with an ether/dichloromethane mixture andtrituration in ether are carried out. The light-beige solid obtained isrecrystallised.

[0912] Melting point=127.7-128.7° C.

[0913] Elemental Microanalysis: C H N % calculated: 70.04 8.08 10.21 %found: 69.74 8.14 10.43

EXAMPLE 114

[0914] Methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate

[0915] The procedure is as in Example 97.

[0916] Starting compound: Preparation 117

EXAMPLE 115

[0917]N-[2-(1,3-Dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-acetamide

[0918] A solution of the product obtained in Preparation 109 (10 mmol)in ether (160 ml) is added very slowly, using a dropper to a solution ofmalonyl dichloride (40 mmol) in ether (40 ml) and triethylamine (2 ml).At the end of the reaction, the reaction mixture is concentrated underreduced pressure. The residue is dried using a vane pump and then takenup in ether. The organic phase is washed with water, dried overmagnesium sulphate, concentrated under reduced pressure and then driedusing a vane pump. The residue is then taken up in 100 ml of1,1,2,2-tetrachloroethane. The resulting solution is then added dropwiseto a solution of aluminium chloride (30 mmol) in 50 ml of the samesolvent under nitrogen. The mixture is heated at 60° C. until thereaction has ceased; the reaction mixture is then poured into a mixtureof ice (20 g) and concentrated HCl (1 ml) and is stirred for one hour.The aqueous phase is extracted twice with chloroform and then thecombined organic phases are dried over magnesium sulphate andconcentrated under reduced pressure. The residue is chromatographed onsilica gel to yield the title product.

[0919] In Examples 116 to 120 the procedure is as in Example 115,starting from appropriate substrates.

EXAMPLE 116

[0920]N-Cyclohexyl-4-(1,3-dioxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butanamide

[0921] Starting compound: Preparation 112

EXAMPLE 117

[0922]N-[2-(7-Benzoyl-1,2-dioxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N′-propylurea

[0923] Starting compound: Preparation 115

EXAMPLE 118

[0924]N-Methyl-4-(7,9-dioxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanamide

[0925] Starting compound: Preparation 119

EXAMPLE 119

[0926]N-{2-[2-(4-Fluorobenzyl)-3-methyl-7,8-dioxo-3,6,7,8-tetrahydro-dipyrrolo[2,3-b:3,2-d]pyridin-1-yl]ethyl}acetamide

[0927] Starting compound: Preparation 122

EXAMPLE 120

[0928]N-[(8,10-Dioxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methyl]acetamide

[0929] Starting compound: Preparation 124

EXAMPLE 121

[0930]N-[2-(3-Oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenyl-acetamide

[0931] The product of Example 115 (3 mmol) is dissolved in acetic acid(70 ml). After several purges with argon, 10% palladium-on-carbon (600mg) is added and the mixture is placed under a hydrogen atmosphere.Stirring is carried out at ambient temperature until the end of thereaction (monitored by TLC) and the palladium is filtered off overCelite. The acetic acid is evaporated off to dryness and the residue ischromatographed on silica gel to yield the title product.

[0932] In Examples 122 to 126 the procedure is as in Example 121,starting from appropriate substrates.

EXAMPLE 122

[0933]N-Cyclohexyl-4-(3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)-butanamide

[0934] Starting compound: Example 116

EXAMPLE 123

[0935]N-[2-(7-Benzoyl-2-oxo-2,3-dihydro-1H-benzo[e]indol-9-yl)ethyl]-N′-propylurea

[0936] Starting compound: Example 117

EXAMPLE 124

[0937]N-Methyl-4-(9-oxo-6,7,8,9-tetrahydrofuro[3,2-f]quinolin-1-yl)-butanamide

[0938] Starting compound: Example 118

EXAMPLE 125

[0939]N-{2-[2-(4-Fluorobenzyl)-3-methyl-8-oxo-3,6,7,8-tetrahydropyrrolo-[2,3-b:3,2-d]pyridin-1-yl]ethyl}acetamide

[0940] Starting compound: Example 119

EXAMPLE 126

[0941]N-[(8-Oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)-methyl]acetamide

[0942] Starting compound: Example 120

EXAMPLE 127

[0943]N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexane-carboxamide

[0944] The product of Example 33 (10 mmol) and triethylene glycol areintroduced into a two-necked flask. Heating is carried out at 160-170°C., under nitrogen and with stirring, for five hours. The reactionmixture is poured into ice-cold water and is extracted with ethylacetate. The organic phase is washed with water and dried over calciumchloride. After filtration, the organic phase is concentrated underreduced pressure. The residue is chromatographed on silica gel to yieldthe title product.

[0945] In Examples 128 to 132, the procedure is as in Example 127,starting from appropriate substrates.

EXAMPLE 128

[0946]N-[2-(2-Benzyl-7-isopropyl-6-oxo-6,7-dihydrothieno[3,2-f]isoquinolin-1-yl)ethyl]acetamide

[0947] Starting compound: Example 37

EXAMPLE 129

[0948]N-[2-(3-Cyclohexyl-4-oxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoquinolin-10-yl)ethyl]acetamide

[0949] Starting compound: Example 40

EXAMPLE 130

[0950]N-[2-(4-Oxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-2-bromo-acetamide

[0951] Starting compound: Example 46

EXAMPLE 131

[0952]N-[2-(2-Benzyl-6-oxo-6,7-dihydrofuro[3,2-f]isoquinolin-1-yl)ethyl]-1-cyclopropanecarboxamide

[0953] Starting compound: Example 49

EXAMPLE 132

[0954]N-[(9-Isopropyl-7-oxo-3-phenyl-3,7,8,9-tetrahydrochromeno[6,5-c]-azepin-2-yl)methyl]butanamide

[0955] Starting compound: Example 50

EXAMPLE 133

[0956]N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)ethyl]-2-phenylacetamide

[0957] Step A:2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl-carbonyl]amino}aceticacid

[0958] A 0.5N aqueous solution of K₂CO₃ (10 ml) is added to the productobtained in Example 39 (4 mmol) dissolved in methanol (10 ml). When thereaction has ceased, the solution is acidified to pH 6-7 using 1Nhydrochloric acid solution. The reaction mixture is extracted withdichloromethane. The organic phase is washed with water, dried overmagnesium sulphate and Is concentrated under reduced pressure. Theresidue is chromatographed on silica gel to yield the title product.

[0959] Step B:2-{[(4-{2-[(2-Phenylacetyl)amino]ethyl}-3,4-dihydro-2H-chromen-6-yl-carbonyl]amino}acetylchloride

[0960] The product obtained in Step A (3 mmol), dissolved in thionylchloride, is stirred at 60° C. under a current of nitrogen for one hour.The thionyl chloride is evaporated off under reduced pressure and theresidue is dried with the aid of a vane pump to yield the title product.

[0961] Step C:N-[2-(1,4-Dioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)-ethyl]-2-phenylacetamide

[0962] The product obtained in Step B (3 mmol), dissolved in1,1,2,2-tetrachloroethane (30 ml), is added dropwise to a solution ofaluminium chloride (10 mmol) in the same solvent (20 ml) under nitrogen.The reaction mixture is heated at 60° C., with stirring, until thereaction has ceased. The solution is then poured into a mixture of ice(10 g)/concentrated HCl (0.3 ml) and stirring is carried out for onehour. The aqueous phase is extracted twice with chloroform; the combinedorganic phases are then dried over magnesium sulphate and concentratedunder reduced pressure. The residue is chromatographed on silica gel toyield the title product.

[0963] In Examples 134 to 135 the procedure is as in Example 133,starting from appropriate reactants.

EXAMPLE 134

[0964]N-[2-(1,4-Dioxo-8-naphthyl-1,2,3,4-tetrahydro[f]isoquinolin-10-yl)-ethyl]heptanamide

[0965] Starting compound: Example 45

EXAMPLE 135

[0966]N-{2-[8-(Cyclopropylmethyl)-1,4-dioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}acetamide

[0967] Starting compound: Example 48

[0968] In Examples 136 to 138 the procedure is as in Example 122,starting from appropriate substrates.

EXAMPLE 136

[0969]N-[2-(4-Oxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)-ethyl]-2-phenylacetamide

[0970] Starting compound: Example 133

EXAMPLE 137

[0971]N-[2-(4-Oxo-8-naphthyl-1,2,3,4-tetrahydrobenzo[f]isoquinolin-10-yl)-ethyl]heptanamide

[0972] Starting compound: Example 134

EXAMPLE 138

[0973]N-{2-[8-(Cyclopropylmethyl)-4-oxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}acetamide

[0974] Starting compound: Example 135

EXAMPLE 139

[0975]N-[2-(4-Thioxo-3,4-dihydrobenzo[f]isoquinolin-10-yl)ethyl]-1-cyclohexanecarbothioamide

[0976] The product obtained in Example 127 is treated with Lawesson'sreagent to yield the title compound. Examples 140 to 142 are obtained byproceeding as in Example 139.

EXAMPLE 140N-[2-(3-Cyclohexyl-4-thioxo-3,8,9,10-tetrahydro-4H-thiopyrano[3,2-f]-isoquinolin-10-yl)ethyl]acetamide

[0977] Starting compound: Example 129

EXAMPLE 141

[0978]N-[2-(1,4-Dithioxo-1,3,4,8,9,10-hexahydro-2H-pyrano[3,2-f]isoquinolin-10-yl)ethyl]-2-phenylethanethioamide

[0979] Starting compound: Example 133

EXAMPLE 142

[0980]N-{2-[8-(Cyclopropylmethyl)-4-thioxo-1,2,3,4-tetrahydrobenzo[f]-isoquinolin-10-yl]ethyl}ethanethioamide

[0981] Starting compound: Example 138

EXAMPLE 143

[0982]N-Cyclohexyl-4-(1-hydroxy-3-oxo-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)butanamide

[0983] A solution of the product obtained in Example 116 (2 mmol)dissolved in methanol (10 ml) is added dropwise to a suspension ofsodium hydride (2.2 mmol) in methanol (50 ml) at −40° C. Stirring iscarried out until the starting compound has completely disappeared(about 3 hours). At the end of the reaction, the solution is poured intowater (30 ml). The reaction mixture is concentrated under reducedpressure to a volume of about 30 ml and is then extracted with ethylacetate. The aqueous phase is washed with water, dried over magnesiumsulphate and concentrated under reduced pressure. The residue ischromatographed on silica gel to yield the title product.

[0984] In Examples 144 and 145, the procedure is as in Example 143.

EXAMPLE 144

[0985]N-[(10-Hydroxy-8-oxo-2,3,7,8,9,10-hexahydro-1H-pyrano[3,2-f]quinolin-2-yl)methyl]acetamide

[0986] Starting compound: Example 120

EXAMPLE 145

[0987]N-[2-(1-Hydroxy-4-methyl-1,2,3,4-tetrahydrobenzo[f]quinolin-10-yl)ethyl]-2-phenylacetamide

[0988] Starting compound: Example 133

EXAMPLE 146

[0989] Methyl 3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate

[0990] The procedure is as in Examples 74 and 75.

EXAMPLE 147

[0991] Methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate

[0992] The procedure is as in Examples 74 and 75.

EXAMPLE 148

[0993] Methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate

[0994] The procedure is as in Example 63.

EXAMPLE 149

[0995] Methyl 3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate

[0996] The procedure is as in Example 63.

EXAMPLE 150

[0997] 3-[2-(Benzoylamino)ethyl]-1-benzofuran-5-carboxamide

[0998] The procedure is as in Example 67.

EXAMPLE 151

[0999] Methyl 8-[2-(3-butenoylamino)ethyl]-2-naphthyl-carbamate

[1000] The procedure is as in Examples 74 and 75.

EXAMPLE 152

[1001] N-{8-[2-(Acetylamino)ethyl]-2-naphthyl}-4-fluorobenzamide

[1002] The procedure is as in Example 1, starting from the compoundobtained in Preparation 117.

EXAMPLE 153

[1003] Ethyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate

[1004] The procedure is as in Example 62.

PHARMACOLOGICAL STUDY EXAMPLE A

[1005] Acute Toxicity Study

[1006] Acute toxicity was evaluated after oral administration to groupseach comprising 8 mice (26±2 grams). The animals were observed atregular intervals during the course of the first day, and daily for thetwo weeks following treatment. The LD₅₀ (dose that causes the death of50% of the animals) was evaluated and demonstrated the low toxicity ofthe compounds of the invention.

EXAMPLE B:

[1007] Melatonin Receptor Binding Study on Pars Tuberalis Cells of Sheep

[1008] Melatonin receptor binding studies of the compounds of theinvention were carried out according to conventional techniques on parstuberalis cells of sheep. The pars tuberalis of the adenohypophysis isin fact characterised in mammals by a high density of melatoninreceptors (Journal of Neuroendocrinology, 1, pp. 1-4, 1989).

[1009] Protocol

[1010] 1) Sheep pars tuberalis membranes are prepared and used as targettissue in saturation experiments to determine the binding capacities andaffinities for 2-[¹²⁵I]-iodomelatonin.

[1011] 2) Sheep pars tuberalis membranes are used as target tissue incompetitive binding experiments using the various test compounds incomparison with melatonin.

[1012] Each experiment is carried out in triplicate and a range ofdifferent concentrations is tested for each compound. The results enablethe determination, after statistical processing, of the bindingaffinities of the compound tested.

[1013] Results

[1014] The compounds of the invention appear to have a strong affinityfor melatonin receptors.

EXAMPLE C

[1015] 1. Melatonin mt₁ and MT₂ Receptor Binding Study

[1016] The mt₁ or MT₂ receptor binding experiments are carried out using2-[¹²⁵I]-melatonin as reference radioligand. The radioactivity retainedis determined using a liquid scintillation counter.

[1017] Competitive binding experiments are then carried out intriplicate using the various test compounds. A range of differentconcentrations is tested for each compound. The results enable thebinding affinities of the compounds tested (IC₅₀) to be determined.

[1018] 2. Study of Binding to MT₃ Melatonin Binding Sites

[1019] The MT₃ site binding experiments are carried out on hamster brainmembranes using 2-[¹²⁵I]-melatonin as reference radioligand. Themembranes are incubated for 30 minutes with the 2-[¹²⁵I]-melatonin at atemperature of 4° C. and at different concentrations of the testcompounds. After incubation, the membranes are quickly filtered and thenwashed with cold buffer using a filtration system. The radioactivityfixed is measured using a scintillation counter. The IC₅₀ values(concentration inhibiting specific binding by 50%) are calculated fromcompetition curves according to a non-linear regression model.

[1020] The IC₅₀ values found for the compounds of the inventiondemonstrate binding to one or other of the receptor sub-types, thevalues being≦10 μM.

EXAMPLE D

[1021] Action of the Compounds of the Invention on the Circadian Rhythmsof Locomotive Activity of the Rat

[1022] The involvement of melatonin in influencing, by day/nightalternation, the majority of physiological, biochemical and behaviouralcircadian rhythms has made it possible to establish a pharmacologicalmodel for research into melatoninergic ligands.

[1023] The effects of the molecules are tested on numerous parametersand, in particular, on the circadian rhythms of locomotive activity,which are a reliable indicator of the endogenous circadian clock.

[1024] In this study, the effects of such molecules on a particularexperimental model, namely the rat placed in temporal isolation(permanent darkness), is evaluated.

[1025] Experimental Protocol

[1026] One-month-old male rats are subjected, as soon as they arrive atthe laboratory, to a light cycle of 12 hours' light per 24 hours (LD12:12).

[1027] After 2 to 3 weeks' adaptation, they are placed in cages fittedwith a wheel connected to a recording system, in order to detect thephases of locomotive activity and thus monitor the nychthemeral rhythms(LD) or circadian rhythms (DD).

[1028] As soon as the rhythms recorded show a stable pattern during thelight cycle LD 12:12, the rats are placed in permanent darkness (DD).

[1029] Two to three weeks later, when the free course (rhythm reflectingthat of the endogenous clock) is clearly established, the rats are givena daily administration of the molecule to be tested.

[1030] The observations are made by means of visualisation of therhythms of activity:

[1031] influence on the rhythms of activity by the light/dark cycle,

[1032] disappearance of the influence on the rhythms in permanentdarkness,

[1033] influence on the activity by the daily administration of themolecule; transitory or durable effect.

[1034] A software package makes it possible:

[1035] to measure the duration and intensity of the activity, the periodof the rhythm of the animals during free course and during treatment,

[1036] possibly to demonstrate by spectral analysis the existence ofcircadian and non-circadian (for example ultradian) components.

[1037] Results

[1038] The compounds of the invention clearly appear to allow powerfulaction on the circadian rhythm via the melatoninergic system.

EXAMPLE E

[1039] Light/Dark Cages Test

[1040] The compounds of the invention are tested on a behavioural model,the light/dark cages test, which allows the anxiolytic activity of thecompounds to be demonstrated.

[1041] The apparatus consists of two polyvinyl boxes covered withPlexiglass. One of the boxes is in darkness. A lamp is placed above theother box, yielding a light intensity of approximately 4000 lux in thecentre of the box. An opaque plastic tunnel separates the light box fromthe dark box. The animals are tested individually for a session of 5minutes. The floor of each box is cleaned between each session. At thestart of each test, the mouse is placed in the tunnel, facing the darkbox. The time spent by the mouse in the illuminated box and the numberof passages through the tunnel are recorded after the first entry intothe dark box.

[1042] After administration of the compounds 30 minutes before the startof the test, the compounds of the invention significantly increase thetime spent in the illuminated cage and the number of passages throughthe tunnel, which demonstrates the anxiolytic activity of the compoundsof the invention.

EXAMPLE F

[1043] Activity of Compounds of the Invention on the Caudal Artery ofthe Rat

[1044] The compounds of the invention were tested in vitro on the caudalartery of the rat. Melatoninergic receptors are present in thosevessels, thus providing a relevant pharmacological model for studyingmelatoninergic ligand activity. The stimulation of the receptors cancause either vasoconstriction or dilation depending on the arterialsegment studied.

[1045] Protocol

[1046] One-month old rats are accustomed to a light/dark cycle of 12h/12 h during a period of 2 to 3 weeks.

[1047] After sacrifice, the caudal artery is isolated and maintained ina highly oxygenated medium. The arteries are then cannulated at bothends, suspended vertically in an organ chamber in a suitable medium andperfused via their proximal end. The pressure changes in the perfusionflow enable evaluation of the vasoconstrictive or vasodilatory effect ofthe compounds.

[1048] The activity of the compounds is evaluated on segments that havebeen pre-contracted by phenylephrine (1 μM). A concentration/responsecurve is determined non-cumulatively by the addition of a concentrationof the test compound to the pre-contracted segment. When the observedeffect reaches equilibrium, the medium is changed and the preparation isleft for 20 minutes before the addition of the same concentration ofphenylephrine and a further concentration of the test compound.

[1049] Results

[1050] The compounds of the invention significantly modify the diameterof caudal arteries pre-constricted by phenylephrine.

EXAMPLE G

[1051] Pharmaceutical Composition: Tablets 1000 tablets each comprising5 mg of methyl  5 g 3-{2-[(cyclopropylcarbonyl)-amino]ethyl}-1-benzofuran-5-yl-carbamate (Example 75) wheat starch 20 gmaize starch 20 g lactose 30 g magnesium stearate  2 g silica  1 ghydroxypropyl cellulose  2 g

We claim:
 1. A compound of formula (I): R-A-R′  (I) wherein: ♦ Arepresents: a ring system of formula (II):

wherein X represents oxygen, sulphur or nitrogen or C(H)_(q) (wherein qis 0, 1 or 2) or NR₀ (wherein R₀ represents hydrogen, linear or branched(C₁-C₆)alkyl, aryl, aryl-(C₁-C₆)alkyl in which the alkyl moiety islinear or branched) or SO₂Ph, Y represents nitrogen or C(H)_(q) (whereinq is 0, 1 or 2), Z represents nitrogen or C(H)_(q) (wherein q is 0, 1 or2), but X, Y and Z cannot represent three hetero atoms simultaneously, Brepresents a benzene or pyridine nucleus, the symbol

means that the bonds may be single or double, it being understood thatthe valency of the atoms is respected, wherein R substitutes the ring Band R′ substitutes the ring containing X, Y and Z, or R and R′substitute the ring B, a ring system of formula (III):

wherein X′ represents oxygen or sulphur or C(H)_(q) (wherein q is 0, 1or 2), Y′ represents C(H)_(q) (wherein q is 0, 1 or 2) or NR₀ wherein R₀is as defined hereinbefore, Z′ represents C(H)_(q) (wherein q is 0, 1 or2) or NR₀ wherein R₀ is as defined hereinbefore, T′ represents oxygen orsulphur or C(H)_(q) (wherein q is 0, 1 or 2), it being understood that,when Y′ or Z′ represents a hetero atom, the other three variables ((X′,Z′, T′) and (X′, Y′, T′), respectively) cannot represent a hetero atom,the symbol

is as defined hereinbefore, B′ represents: benzene, naphthalene when X′,Y′, Z′ and T′ do not simultaneously represent C(H)_(q) (wherein q is 0,1 or 2), or pyridine when X′ and T′ simultaneously represent C(H)_(q)(wherein q is 0, 1 or 2), wherein R substitutes the ring B′ and R′substitutes the ring containing X′, Y′, Z′ and T′, or R and R′substitute the ring B′, a ring system of formula (IV):

representing the ring systems (IV_(a-d))

wherein n is an integer such that 0≦n≦3, W represents oxygen, sulphur ornitrogen, or [C(H)_(q)]_(p) (wherein q is 0, 1 or 2, and p is 1 or 2) orNR₀ wherein R₀ is as defined hereinbefore, the symbol

is as defined hereinbefore, wherein R′ substitutes the ring

and R substitutes one or other of the two other rings, or biphenylwherein R substitutes one of the benzene rings and R′ substitutes theother, or R and R′ substitute the same benzene ring, it being understoodthat the ring systems of formulae (II), (III) and (IV) and the biphenylgroup may be unsubstituted or substituted (in addition to thesubstituents R and R′) by from 1 to 6 radicals, which may be the same ordifferent, selected from R_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a),OSO₂CF₃ and halogen, wherein R_(a) represents hydrogen, unsubstituted orsubstituted linear or branched (C₁-C₆)alkyl, unsubstituted orsubstituted linear or branched (C₂-C₆)alkenyl, unsubstituted orsubstituted linear or branched (C₂-C₆)alkynyl, linear or branched(C₁-C₆)polyhaloalkyl, unsubstituted or substituted (C₃-C₈)cycloalkyl,unsubstituted or substituted (C₃-C₈)cycloalkyl-(C₁-C₆)alkyl in which thealkyl group is linear or branched, unsubstituted or substituted(C₃-C₈)cycloalkenyl, unsubstituted or substituted(C₃-C₈)cycloalkenyl-(C₁-C₆)alkyl in which the alkyl group is linear orbranched, aryl, aryl-(C₁-C₆)alkyl in which the alkyl moiety is linear orbranched, aryl-(C₁-C₆)alkenyl in which the alkenyl moiety is linear orbranched, heteroaryl, heteroaryl-(C₁-C₆)alkyl in which the alkyl moietyis linear or branched, heteroaryl-(C₁-C₆)alkenyl in which the alkenylmoiety is linear or branched, unsubstituted or substituted linear orbranched (C₁-C₆)heterocycloalkyl, unsubstituted or substitutedheterocycloalkenyl, substituted or unsubstitutedheterocycloalkyl-(C₁-C₆)alkyl in which the alkyl moiety is linear orbranched, or substituted or unsubstitutedheterocycloalkenyl-(C₁-C₆)alkyl in which the alkyl moiety is linear orbranched, ♦ R represents: a group of formula (V):

wherein Q represents sulphur or oxygen, R′ represents NR′_(a)R″_(a) orOR¹ _(a) (wherein R′_(a) and R″_(a), which may be the same or different,may take any of the values of R_(a) and may also form, together with thenitrogen atom carrying them, a 5- to 10-membered cyclic group which maycontain, in addition to the nitrogen atom by which it is linked, fromone to three hetero atoms selected from oxygen, sulphur and nitrogen,and R¹ _(a) may take any of the values of R_(a) except for the hydrogenatom), a group of formula (VI):

wherein R² represents R_(a) as defined hereinbefore, R³ representsCOR′_(a), CSR′_(a), CONR′_(a)R″_(a), CSNR′_(a)R′_(a), COOR′_(a),CSOR′_(a) or S(O)_(v)R′_(a) (wherein R′_(a) and R″_(a), which may be thesame or different, are as defined hereinbefore and may also form,together with the nitrogen atom carrying them, a cyclic group as definedhereinbefore, and v is 1 or 2), a group of formula (VII):

wherein v is as defined hereinbefore and R⁴ represents NR′_(a)R″_(a),NR_(a)COR′_(a), NR_(a)CSR′_(a), NR_(a)CONR′_(a)R″_(a),NR_(a)CSNR′_(a)R′_(a) or NR_(a)COOR′_(a), wherein R_(a), R′_(a and R″)_(a) are as defined hereinbefore, or, when A represents a ring system offormula (II) or (III) or biphenyl, forms, together with two adjacentcarbon atoms of the cyclic structure A carrying it, a ring of formula(VIII):

the ring formed containing from 5 to 7 atoms and it being possible forthe said ring to contain from 1 to 3 hetero atoms selected fromnitrogen, sulphur and oxygen, and one or more unsaturations, and beingoptionally substituted by one or more radicals, which may be the same ordifferent, selected from R_(a), OR_(a), COR_(a), COOR_(a), OCOR_(a),NR′_(a)R″_(a), NR_(a)COR′_(a), CONR′_(a)R″_(a), cyano, oxo, SR_(a),S(O)R_(a), SO₂R_(a), CSR_(a), NR_(a)CSR′_(a), CSNR′_(a)R″_(a),NR_(a)CONR′_(a)R″_(a), NR_(a)CSNR′_(a)R″_(a) and halogen, wherein R_(a),R′_(a) and R″_(a), which may be the same or different, are as definedhereinbefore and R′_(a) and R″_(a) may also form, together with thenitrogen atom carrying them, a cyclic group as defined hereinbefore, ♦and R′ represents a group of formula (IX): -G-R⁵   (IX) wherein Grepresents an alkylene chain —(CH₂)_(t)— (wherein t is an integer suchthat 0≦t≦4 when A represents a tricyclic structure and such that 1≦t≦4when A represents a bicyclic structure), optionally substituted by oneor more radicals, which may be the same or different, selected fromR_(a), OR_(a), COOR_(a), COR_(a) (in which R_(a) is as definedhereinbefore) or halogen, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) (which may be the same or different)are as defined hereinbefore, it being possible for R′_(a) and R″_(a) toform, together with the nitrogen atom carrying them, a cyclic group asdefined hereinbefore, it being understood that: “heterocycloalkyl” istaken to mean any saturated mono- or poly-cyclic group containing from 5to 10 atoms containing from 1 to 3 hetero atoms selected from nitrogen,oxygen and sulphur, “heterocycloalkenyl” is taken to mean anynon-aromatic mono- or poly-cyclic group containing one or moreunsaturations, containing from 5 to 10 atoms and which may contain from1 to 3 hetero atoms selected from nitrogen, oxygen and sulphur, the term“substituted” used in respect of the expressions “alkyl”, “alkenyl” and“alkynyl” indicates that the groups in question are substituted by oneor more radicals, which may be the same or different, selected fromhydroxy, linear or branched (C₁-C₆)alkoxy, linear or branched(C₁-C₆)alkyl, linear or branched (C₁-C₆)polyhaloalkyl, amino andhalogen, the term “substituted” used in respect of the expressions“cycloalkyl”, “cycloalkylalkyl”, “cycloalkenyl”, “cycloalkenylalkyl”,“heterocycloalkyl”, “heterocycloalkenyl”, “heterocycloalkylalkyl” and“heterocycloalkenylalkyl” indicates that the cyclic moiety of the groupsin question is substituted by one or more radicals, which may be thesame or different, selected from hydroxy, linear or branched(C₁-C₆)alkoxy, linear or branched (C₁-C₆)alkyl, linear or branched(C₁-C₆)polyhaloalkyl, amino and halogen, “aryl” is taken to mean anyaromatic, mono- or poly-cyclic group containing from 6 to 22 carbonatoms, and also the biphenyl group, “heteroaryl” is taken to mean anyaromatic mono- or poly-cyclic group containing from 5 to 10 atomscontaining from 1 to 3 hetero atoms selected from nitrogen, oxygen andsulphur, it being possible for the “aryl” and “heteroaryl” groups to besubstituted by one or more radicals, which may be the same or different,selected from hydroxy, linear or branched (C₁-C₆)alkoxy, linear orbranched (C₁-C₆)alkyl, linear or branched (C₁-C₆)polyhaloalkyl, cyano,carboxy, nitro, amino and halogen, it being understood that: when Arepresents indole, there cannot be any substituents in the 2-position,when A represents indole and R represents —NHCOR′_(a), —NHCOOR′_(a) orNHCONR′_(a)R″_(a), then G-R⁵ cannot represent —(CH₂)₂—NHCOR_(b) whereinR_(b) represents (C₁-C₄)alkyl or CF₃, when A represents benzofuran orbenzothiophene, there cannot be any COPh (wherein Ph is substituted orunsubstituted) in the 2-position, when A represents benzofuran orbenzothiophene, R cannot represent —NR_(a)COR_(c), —NHSO₂R_(c),—NHCOCH₂R_(c) or NHCONHR_(c) wherein R_(c) represents heterocyclic oraryl, when A represents tetrahydronaphthalene, R⁵ cannot representCONR′_(a)R″_(a), when A represents hydrocarbon ring system and R⁵represents NHCOR′_(a), then R cannot represent COOR′_(a), the compoundof formula (I) cannot represent:N-{8-[(acetylamino)methyl]-2-naphthyl}-2-methylpropanamide,N-(2-{5-[(4-ethoxyanilino)sulphonyl]-1H-indol-3-yl}ethyl)acetamide,8-[(acetylamino)methyl]-N-isopropyl-2-naphthamide, its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 2. A compound of formula (I) according to claim1, wherein A represents a ring system of formula (II′):

wherein B, X and the symbol

are as defined in claim 1, its enantiomers and diastereoisomers, andaddition salts thereof with a pharmaceutically acceptable acid or base.3. A compound of formula (I) according to claim 1, wherein A representsa ring system of formula (III′):

wherein B′, X′, T′ and the symbol

are as defined in claim 1, its enantiomers and diastereoisomers, andaddition salts thereof with a pharmaceutically acceptable acid or base.4. A compound of formula (I) according to claim 1, wherein A representsa ring system of formula (II′) substituted in the 5-position by R asdefined in claim 1 and in the 3-position by R′ as defined in claim 1,its enantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 5. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′) substituted in the 7-position by R as defined in claim 1 and inthe 1- or 2-position by R′ as defined in claim 1, its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 6. A compound of formula (I) according to claim1, wherein R represents a group of formula (V), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 7. A compound of formula (I) according to claim1, wherein R represents a group of formula (VI), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 8. A compound of formula (I) according to claim1, wherein R represents a group of formula (VII), its enantiomers anddiastereolsomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 9. A compound of formula (I) according to claim1, wherein R represents a group of formula (V) wherein Q representsoxygen and R¹ represents NR′_(a)R″_(a) as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 10. A compound of formula (I)according to claim 1, wherein R represents a group of formula (V)wherein Q represents oxygen and R¹ represents OR¹ _(a) as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 11. A compoundof formula (I) according to claim 1, wherein R represents a group offormula (VI) wherein R³ represents COR′_(a) wherein R′_(a) is as definedin claim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 12. A compoundof formula (I) according to claim 1, wherein R represents a group offormula (VI) wherein R³ represents COOR′_(a) wherein R′_(a) is asdefined in claim 1, its enantiomers and diastereoisomers, and additionsalts thereof with a pharmaceutically acceptable acid or base.
 13. Acompound of formula (I) according to claim 1, wherein R represents agroup of formula (VII) wherein v is 2 and R⁴ represents NR′_(a)NR″_(a),its enantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 14. A compound of formula (I)according to claim 1, wherein R′ represents G-R⁵ wherein G represents anunsubstituted or substituted alkylene chain —(CH₂)_(t)— wherein t is 2or 3 and R⁵ represents

wherein R_(a), R′_(a), R″_(a) and Q are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 15. A compound of formula (I)according to claim 1, wherein R′ represents G-R⁵ wherein G represents analkylene chain —(CH₂)_(t)— wherein t is 2 or 3 and R⁵ represents—NHCOR′_(a) or —CONHR′_(a) wherein R′_(a) is as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 16. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′) and R represents a group of formula (V), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 17. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (II′) and Rrepresents a group of formula (VI), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 18. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (III′) and Rrepresents a group of formula (VII), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 19. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (III′) and Rrepresents a group of formula (V), its enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 20. A compound of formula (I) according to claim 1, wherein Arepresents a ring system of formula (III′) and R represents a group offormula (VI), its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 21. A compoundof formula (I) according to claim 1, wherein A represents a ring systemof formula (III′) and R represents a group of formula (VII), itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 22. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′) substituted in the 5-position by a group of formula (V) and in the3-position by a group of formula (IX), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 23. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (II′) substitutedin the 5-position by a group of formula (V) and in the 3-position by agroup of formula (IX), its enantiomers and diastereoisomers, andaddition salts thereof with a pharmaceutically acceptable acid or base.24. A compound of formula (I) according to claim 1, wherein A representsa ring system of formula (II′) substituted in the 5-position by a groupof formula (VII) and in the 3-position by a group of formula (IX), itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 25. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′) substituted in the 7-position by a group of formula (V) and inthe 1- or 2-position by a group of formula (IX), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 26. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (III′)substituted in the 7-position by a group of formula (VI) and in the 1-or 2-position by a group of formula (IX), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 27. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (III′)substituted in the 7-position by a group of formula (VII) and in the 1-or 2-position by a group of formula (IX), its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 28. A compound of formula (I) according toclaim 1, wherein A represents a ring system of formula (II′), which issubstituted in the 5-position by —CONR′_(a)R″_(a) wherein R′_(a) andR″_(a) are as defined in claim 1 and substituted in the 3-position by agroup of formula (IX) wherein G represents an unsubstituted orsubstituted chain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents

wherein Q, R_(a) R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 29. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′), which are substituted in the 5-position by —SO₂NR′_(a)R″_(a)wherein R′_(a) and R′_(a) are as defined in claim 1 and substituted inthe 3-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 30. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′) substituted in the 5-position by —NHCOR′_(a) wherein R′_(a) is asdefined in claim 1 and which is substituted in the 3-position by a groupof formula (IX) wherein G represents an unsubstituted or substitutedchain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 31. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′), which is substituted in the 5-position by —NHCOOR′_(a) whereinR′_(a) is as defined in claim 1 and substituted in the 3-position by agroup of formula (IX) wherein G represents an unsubstituted orsubstituted chain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 32. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(II′), which is substituted in the 5-position by COOR¹ _(a) wherein R¹_(a) is as defined in claim 1 and substituted in the 3-position by agroup of formula (IX) wherein G represents an unsubstituted orsubstituted chain —(CH₂)_(t)—, wherein t is 2 or 3, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 33. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′), which is substituted in the 7-position by a group of formula—CONR′_(a)R″_(a) wherein R′_(a) and R″_(a) are as defined in claim 1 andsubstituted in the 1- or 2-position by a group of formula (IX) wherein Grepresents an unsubstituted or substituted chain —(CH₂)_(t)—, wherein tis 2 or 3, and R⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 34. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′), which is substituted in the 7-position by —SO₂NR′_(a)R′_(a)wherein R′_(a) and R″_(a) are as defined in claim 1 and substituted inthe 1- or 2-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 35. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′), which is substituted in the 7-position by a group —NHCOR′_(a)wherein R′_(a) is as defined in claim 1 and substituted in the 1- or2-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 36. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′) substituted in the 7-position by a group —NHCOOR′_(a) whereinR′_(a) is as defined in claim 1 and which is substituted in the 1- or2-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 37. A compound of formula (I)according to claim 1, wherein A represents a ring system of formula(III′) substituted in the 7-position by a group COOR¹ _(a) wherein R¹_(a) is as defined in claim 1 and which is substituted in the 1- or2-position by a group of formula (IX) wherein G represents anunsubstituted or substituted chain —(CH₂)_(t)—, wherein t is 2 or 3, andR⁵ represents

wherein Q, R_(a), R′_(a) and R″_(a) are as defined in claim 1, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 38. A compound of formula (I)according to claim 1, wherein A represents naphthalene, dihydro- ortetrahydro-naphthalene, which is optionally substituted (in addition tothe substituents R and R′), preferably in the 3-position, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 39. A compound of formula (I)according to claim 1, wherein A represents benzofuran ordihydrobenzofuran, which is optionally substituted (in addition to thesubstituents R and R′), preferably in the 2-position, its enantiomersand diastereoisomers, and addition salts-thereof with a pharmaceuticallyacceptable acid or base.
 40. A compound of formula (I) according toclaim 1, wherein A represents benzothiophene or dihydrobenzothiophene,which is optionally substituted (in addition to the substituents R andR′), preferably in the 2-position, its enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 41. A compound of formula (I) according to claim 1, wherein Arepresents indole or indoline, which is optionally substituted (inaddition to the substituents R and R′), preferably in the 2-position,its enantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 42. A compound of formula (I)according to claim 1, wherein A represents azaindole optionallysubstituted (in addition to the substituents R and R′), preferably inthe 2-position, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 43. A compoundof formula (I) according to claim 1, wherein A represents naphthalene,dihydro- or tetrahydro-naphthalene, which is optionally substituted (inaddition to the substituents R and R′) in the 3-position, substituted inthe 7-position by —NHCOR_(a), SO₂NHR_(a), COOR¹ _(a) or CONHR_(a)wherein R_(a) and R¹ _(a) are as defined in claim 1, and substituted inthe 1-position by —(CH₂)_(t)—NHCOR′_(a) or —(CH₂)_(t)—CONHR′_(a),wherein t is 2 or 3 and R′_(a) is as defined in claim 1, its enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 44. A compound of formula (I) according toclaim 1, wherein A represents benzofuran or dihydrobenzofuran, which isoptionally substituted (in addition to the substituents R and R′) in the2-position, substituted in the 5-position by —NHCOR_(a), SO₂NHR_(a),COOR¹ _(a) or CONHR_(a) wherein R_(a) and R¹ _(a) are as defined inclaim 1, and substituted in the 3-position by —(CH₂)_(t)—NHCOR+_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 45. A compoundof formula (I) according to claim 1, wherein A represents benzothiopheneor dihydrobenzothiophene, which is optionally substituted (in additionto the substituents R and R′) in the 2-position, substituted in the5-position by —NHCOR_(a), SO₂NHR_(a), COOR¹ _(a) or CONHR_(a) whereinR_(a) and R¹ _(a) are as defined in claim 1, and substituted in the3-position by —(CH₂)_(t)—NHCOR′_(a) or —(CH₂)_(t)—CONHR′_(a), wherein tis 2 or 3 and R′_(a) is as defined in claim 1, its enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 46. A compound of formula (I) according toclaim 1, wherein A represents indole or indoline, which is optionallysubstituted (in addition to the substituents R and R′) in the2-position, substituted in the 5-position by —NHCOR_(a), SO₂NHR_(a),COOR¹ _(a) or CONHR_(a) wherein R_(a) and R¹ _(a) are as defined inclaim 1, and substituted in the 3-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 47. A compoundof formula (I) according to claim 1, wherein A represents azaindole,which is optionally substituted (in addition to the substituents R andR′) in the 2-position, substituted in the 5-position by —NHCOR_(a),SO₂NHR_(a), COOR¹ _(a) or CONHR_(a) wherein R_(a) and R¹ _(a) are asdefined in claim 1, and substituted in the 3-position by—(CH₂)_(t)—NHCOR′_(a) or —(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 andR′_(a) is as defined in claim 1, its enantiomers and diastereoisomers,and addition salts thereof with a pharmaceutically acceptable acid orbase.
 48. A compound of formula (I) according to claim 1, wherein Arepresents naphthalene, dihydronaphthalene or tetrahydronaphthalene,which is optionally substituted (in addition to the substituents R andR′) in the 3-position, substituted in the 7-position by —NHCOOR_(a) or

wherein R_(a) is as defined in claim 1 and alk represents alkyl, andsubstituted in the 1-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 49. A compoundof formula (I) according to claim 1, wherein A represents benzofuran ordihydrobenzofuran, which is optionally substituted (in addition to thesubstituents R and R′) in the 2-position, substituted in the 5-positionby —NHCOOR_(a) or

wherein R_(a) is as defined in claim 1 and alk represents alkyl, andsubstituted in the 3-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 50. A compoundof formula (I) according to claim 1, wherein A represents benzothiopheneor dihydrobenzothiophene, which is optionally substituted (in additionto the substituents R and R′) in the 2-position, substituted in the5-position by —NHCOOR_(a) or

wherein R_(a) is as defined in claim 1 and alk represents alkyl, andsubstituted in the 3-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 51. A compoundof formula (I) according to claim 1, wherein A represents indole orindoline, which is optionally substituted (in addition to thesubstituents R and R′) in the 2-position, substituted in the 5-positionby —NHCOOR_(a) or

wherein R_(a) is as defined in claim 1 and alk represents alkyl, andsubstituted in the 3-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 52. A compoundof formula (I) according to claim 1, wherein A represents azaindole,which is optionally substituted (in addition to the substituents R andR′) in the 2-position, substituted in the 5-position by —NHCOOR_(a) or

wherein R_(a) is as defined in claim 1 and alk represents alkyl, andsubstituted in the 3-position by —(CH₂)_(t)—NHCOR′_(a) or—(CH₂)_(t)—CONHR′_(a), wherein t is 2 or 3 and R′_(a) is as defined inclaim 1, its enantiomers and diastereoisomers, and addition saltsthereof with a pharmaceutically acceptable acid or base.
 53. A compoundof formula (I) according to claim 1 that isN-{2-[6-(acetylamino)-2,3-dihydro-1H-1-indenyl]ethyl}acetamide, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 54. Compounds of formula (I)according to claim 1 that are methyl3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxylate, methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxylate,methyl 3-[2-(3-butenoylamino)ethyl]-1-benzofuran-5-carboxylate, methyl3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxylate, methyl3-[2-(isobutylamino)ethyl]-1-benzofuran-5-carboxylate, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 55. Compounds of formula (I) according to claim1 that are:N,N-diphenyl-3-[3-(acetylamino)propyl]benzo[b]furan-5-carboxamide,3-[2-(acetylamino)ethyl]-1-benzofuran-5-carboxamide,3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-carboxamide,3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-carboxamide,3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,3-[2-(acetylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,3-{2-[(cyclopentylcarbonyl)amino]ethyl}-N-methyl-1-benzofuran-5-carboxamide,3-[2-(benzoylamino)ethyl]-N-methyl-1-benzofuran-5-carboxamide,3-{2-[(cyclopropylcarbonyl)amino]ethyl}-N-ethyl-1-benzofuran-5-carboxamide,3-[2-(benzoylamino)ethyl]-N-ethyl-1-benzofuran-5-carboxamide,3-[2-(acetylamino)ethyl]-N-methyl-1H-pyrrolo[2,3-b]pyridine-5-carboxamide,N-isopropyl-N-(2-propynyl)-3-[(acetylamino)methyl]-2-benzylbenzo[b]thiophene-5-carboxamide,3-[2-(benzoylamino)ethyl]-1-benzofuran-5-carboxamide, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 56. Compounds of formula (I) according to claim1 that are:N-{3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl}-2,2,2-trifluoroacetamide,N-{2-[5-(acetylamino)-1-benzofuran-3-yl]ethyl}cyclopropanecarboxamide,N-{2-[5-(acetylamino)-1-benzothiophen-3-yl]ethyl}benzamide, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 57. Compounds of formula (I)according to claim 1 that are:N-{8-[2-([2-phenylacetyl]amino)ethyl]-2-naphthyl}butanamide,N-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)-1-cyclohexanecarboxamide,N-{8-[2-(heptanoylamino)ethyl]-2,6-dinaphthyl}-2-butenamide,N-{8-[2-(acetylamino)ethyl]-2-naphthyl}acetamide, their enantiomers anddiastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 58. Compounds of formula (I) according to claim1 that are N-ethyl-8-{2-[(2-phenylacetyl)amino]ethyl}-2-naphthamide,N,N-diethyl-8-{2-[2-[(cyclopropylmethyl)amino]-2-oxoethyl}-2-naphthamide,N-phenyl-8-(2-{methyl[(propylamino)carbonyl]amino}ethyl)-2-naphthamide,N-benzyl-1-{2-[(2,2,2-trifluoroacetyl)amino]ethyl}-2-naphthamide,N-(2-{7-[(methylamino)carbonyl]-1-naphthyl}ethyl)-2-furamide, theirenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 59. Compounds of formula (I)according to claim 1 that are:N-{2-[7-(aminosulphonyl)-1-naphthyl]ethyl}acetamide,N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)acetamide,N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethyl)-2-furamide,N-(2-{7-[(ethylamino)sulphonyl]-1-naphthyl}ethyl)benzamide,N-(2-{7-[(methylamino)sulphonyl]-1-naphthyl}ethylcyclopropanecarboxamide,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 60. Compounds of formula (I)according to claim 1 that are:N-(3-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}propyl)acetamide,N-(2-{5-[(propylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)acetamide,N-(2-{5-[(cyclopropylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)benzamide,N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)-2-furamide,N-(2-{5-[(methylamino)sulphonyl]-1-benzofuran-3-yl}ethyl)cyclopropanecarboxamide,N-(2-{2-benzyl-5-[(methylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)acetamide,N-(2-{5-[(isopropylamino)sulphonyl]-1-benzothiophen-3-yl}ethyl)cyclopropane-carboxamide,N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)acetamide,N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)cyclopropane-carboxamide,N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)benzamide,N-(2-{5-[(methylamino)sulphonyl]-1H-pyrrolo[2,3-b]pyridin-3-yl}ethyl)-2-furamidetheir enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 61. Compounds of formula (I)according to claim 1 that are: methylN-{3-[2-(acetylamino)ethyl]benzo[b]furan-5-yl}carbamate, methyl3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-carbamate,tert-butyl 3-[2-(acetylamino)ethyl]-1-benzofuran-5-yl-(methyl)carbamate,methyl 3-[2-(benzoylamino)ethyl]-1-benzofuran-5-yl-carbamate, methyl3-[2-(isobutyrylamino)ethyl]-1-benzofuran-5-yl-carbamate, methyl3-[2-(2-furoylamino)ethyl]-1-benzofuran-5-yl-carbamate, methyl3-{2-[(cyclopentylcarbonyl)amino]ethyl}-1-benzofuran-5-yl-carbamate,their enantiomers and diastereoisomers, and addition salts thereof witha pharmaceutically acceptable acid or base.
 62. A compound of formula(I) according to claim 1 that is methyl5-[(acetylamino)methyl]-2,3-dihydro-1,4-benzodioxin-6-yl-carbamate, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 63. A compound of formula (I)according to claim 1 that is methyl3-[(acetylamino)methyl]-3,4-dihydro-2H-chromen-6-yl-carbamate, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 64. A compound of formula (I)according to claim 1 that is ethyl3-[2-(acetylamino)ethyl]-2,3-dihydro-1H-inden-5-yl-carbamate, itsenantiomers and diastereoisomers, and addition salts thereof with apharmaceutically acceptable acid or base.
 65. Compounds of formula (I)according to claim 1 that are: methyl3-[2-(acetylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate, methyl3-[2-(2-furoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,methyl3-[2-(benzoylamino)ethyl]-1H-pyrrolo[2,3-b]pyridin-5-yl-carbamate,methyl 3-{2-[(cyclopropylcarbonyl)amino]ethyl}-1H-pyrrolo[2,3-b]pyridin-5-yl carbamate, their enantiomers and diastereoisomers, andaddition salts thereof with a pharmaceutically acceptable acid or base.66. Compounds of formula (I) according to claim 1 that are: ethylN-(8-{2-[(2-bromoacetyl)amino]ethyl}-2-naphthyl)carbamate, methylN-{8-[2-(acetylamino)ethyl]-6-phenyl-2-naphthyl}carbamate, hexylN-{8-[2-(acetylamino)ethyl]-5,6,7,8-tetrahydro-2-naphthyl}carbamate,methyl 8-[2-(acetylamino)ethyl]-2-naphthyl-carbamate, their enantiomersand diastereoisomers, and addition salts thereof with a pharmaceuticallyacceptable acid or base.
 67. A method for treating a living bodyafflicted with disorders of the melatoninergic system comprising thestep of administering to the living body an amount of a compound ofclaims 1 to 66 which is effective for the alleviation for saidcondition.
 68. A pharmaceutical composition useful for treatingmelatoninergic disorders comprising, as active principle an effectiveamount of a compound as claimed in claims 1 to 66, together with one ormore pharmaceutically acceptable excipients or vehicles.